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BT 15.000 718.042 Td /F2 21.0 Tf  [(Genetic testing for long QT syndrome and the category of )] TJ ET
BT 15.000 693.094 Td /F2 21.0 Tf  [(cardiac ion channelopathies)] TJ ET
Q
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BT 15.000 675.088 Td /F3 9.8 Tf  [(May 3, 2012)] TJ ET
BT 68.888 675.088 Td /F3 9.8 Tf  [(�)] TJ ET
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BT 73.763 675.088 Td /F3 9.8 Tf  [(Diagnostic)] TJ ET
BT 26.250 663.247 Td /F1 9.8 Tf  [(Stephen M. Modell)] TJ ET
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BT 107.536 663.247 Td /F1 9.8 Tf  [(, )] TJ ET
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BT 112.957 663.247 Td /F1 9.8 Tf  [(David J. Bradley)] TJ ET
0.271 0.267 0.267 rg
BT 183.937 663.247 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 189.358 663.247 Td /F1 9.8 Tf  [(Michael H. Lehmann)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 651.342 Td /F1 9.8 Tf  [(Modell SM, Bradley DJ, Lehmann MH. Genetic testing for long QT syndrome and the category of cardiac ion channelopathies. )] TJ ET
BT 26.250 639.438 Td /F1 9.8 Tf  [(PLOS Currents Evidence on Genomic Tests. 2012 May 3 . Edition 1. doi: 10.1371/4f9995f69e6c7.)] TJ ET
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BT 26.250 610.335 Td /F4 12.0 Tf  [(Abstract)] TJ ET
BT 26.250 590.381 Td /F1 9.8 Tf  [(Cardiac ion channel mutational analysis is a category of genetic testing used in clinical practice for determining the status of )] TJ ET
BT 26.250 578.476 Td /F1 9.8 Tf  [(long QT syndrome, short QT syndrome, catecholaminergic polymorphic ventricular tachycardia, and Brugada syndrome genes )] TJ ET
BT 26.250 566.571 Td /F1 9.8 Tf  [(in blood, saliva, or tissue from patients and family members at risk for cardiac events such as syncope and sudden death. Such )] TJ ET
BT 26.250 554.667 Td /F1 9.8 Tf  [(testing is most informative following careful phenotypic characterization. Individuals with ion channelopathies may benefit from )] TJ ET
BT 26.250 542.762 Td /F1 9.8 Tf  [(prevention \(avoidance of triggers and predisposing drugs\) and treatment \(e.g., beta blocker therapy, implantable cardioverter-)] TJ ET
BT 26.250 530.857 Td /F1 9.8 Tf  [(defibrillator \(ICD\) placement\) modalities.)] TJ ET
BT 26.250 494.255 Td /F4 12.0 Tf  [(Funding Statement)] TJ ET
BT 26.250 474.300 Td /F1 9.8 Tf  [(Funding for this project was made possible by the National Office of Public Health Genomics, Centers for Disease Control and )] TJ ET
BT 26.250 462.396 Td /F1 9.8 Tf  [(Prevention through McKing Consulting Corporation, contract # 200-2009-F-32675.)] TJ ET
BT 26.250 433.293 Td /F4 12.0 Tf  [(Clinical Scenario)] TJ ET
BT 26.250 413.339 Td /F1 9.8 Tf  [(In patients with fainting \(especially occurring during physical exertion or emotional/auditory arousal\), seizures, a history of )] TJ ET
BT 26.250 401.434 Td /F1 9.8 Tf  [(aborted cardiac arrest, a family history of sudden death, or who have themselves succumbed to sudden cardiac death \(SCD\), )] TJ ET
BT 26.250 389.529 Td /F1 9.8 Tf  [(cardiac ion channel mutation testing, typically in conjunction with electrocardiography, can provide important information. )] TJ ET
BT 26.250 377.625 Td /F1 9.8 Tf  [(Performed with cardiac evaluation, genetic testing may be used to determine the status of long QT syndrome \(LQTS\), short QT )] TJ ET
BT 26.250 365.720 Td /F1 9.8 Tf  [(syndrome \(SQTS\), catecholaminergic polymorphic ventricular tachycardia \(CPVT\), and Brugada syndrome \(BrS\) genes from )] TJ ET
BT 26.250 353.815 Td /F1 9.8 Tf  [(blood, saliva, or tissue specimens, including postmortem samples)] TJ ET
0.267 0.267 0.267 rg
BT 309.098 355.322 Td /F4 8.7 Tf  [(1)] TJ ET
BT 313.916 355.322 Td /F4 8.7 Tf  [(2)] TJ ET
BT 318.735 355.322 Td /F4 8.7 Tf  [(3)] TJ ET
0.271 0.267 0.267 rg
BT 323.554 353.815 Td /F1 9.8 Tf  [(. While these conditions demonstrate characteristic )] TJ ET
BT 26.250 341.910 Td /F1 9.8 Tf  [(electrocardiographic patterns \(LQTS � a prolonged QT interval on resting ECG \(part of the Schwartz-Moss diagnostic score\))] TJ ET
0.267 0.267 0.267 rg
BT 561.077 343.418 Td /F4 8.7 Tf  [(4)] TJ ET
0.271 0.267 0.267 rg
BT 565.895 341.910 Td /F1 9.8 Tf  [(; )] TJ ET
BT 26.250 330.006 Td /F1 9.8 Tf  [(CPVT � ventricular ectopy)] TJ ET
0.267 0.267 0.267 rg
BT 139.496 331.513 Td /F4 8.7 Tf  [(5)] TJ ET
0.271 0.267 0.267 rg
BT 144.315 330.006 Td /F1 9.8 Tf  [(; BrS � ST segment elevation)] TJ ET
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BT 271.123 331.513 Td /F4 8.7 Tf  [(2)] TJ ET
0.271 0.267 0.267 rg
BT 275.942 330.006 Td /F1 9.8 Tf  [(\), these findings may be absent or inconclusive on a single clinical )] TJ ET
BT 26.250 318.101 Td /F1 9.8 Tf  [(test. Similarly, post-mortem samples may be accompanied by insufficient clinical data for diagnostic classification. Genetic )] TJ ET
BT 26.250 306.196 Td /F1 9.8 Tf  [(testing has been used to exclude one condition over another and to provide definitive diagnosis in many such situations)] TJ ET
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BT 540.562 307.703 Td /F4 8.7 Tf  [(1)] TJ ET
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BT 555.019 306.196 Td /F1 9.8 Tf  [(. For )] TJ ET
BT 26.250 294.291 Td /F1 9.8 Tf  [(the patient whose symptoms, ECG, and/or other adjunctive tests)] TJ ET
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BT 304.252 295.799 Td /F4 8.7 Tf  [(5)] TJ ET
BT 309.070 295.799 Td /F4 8.7 Tf  [(8)] TJ ET
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BT 313.889 294.291 Td /F1 9.8 Tf  [( have led to a clinical diagnosis, the test can identify pertinent )] TJ ET
BT 26.250 282.387 Td /F1 9.8 Tf  [(risks and assist management. In addition, relatives of affected patients, who may have no symptoms but are capable of passing )] TJ ET
BT 26.250 270.482 Td /F1 9.8 Tf  [(on an abnormal gene, can be identified through techniques like cascade screening)] TJ ET
0.267 0.267 0.267 rg
BT 381.774 271.989 Td /F4 8.7 Tf  [(1)] TJ ET
BT 386.593 271.989 Td /F4 8.7 Tf  [(3)] TJ ET
BT 391.411 271.989 Td /F4 8.7 Tf  [(6)] TJ ET
BT 396.230 271.989 Td /F4 8.7 Tf  [(9)] TJ ET
0.271 0.267 0.267 rg
BT 401.049 270.482 Td /F1 9.8 Tf  [(. Therapies for patients displaying )] TJ ET
BT 26.250 258.577 Td /F1 9.8 Tf  [(mutations include avoidance of physical triggers and aggravating drugs, placement on anti-arrhythmic drug or beta blocker )] TJ ET
BT 26.250 246.672 Td /F1 9.8 Tf  [(therapy)] TJ ET
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BT 58.766 248.180 Td /F4 8.7 Tf  [(10)] TJ ET
BT 68.404 248.180 Td /F4 8.7 Tf  [(11)] TJ ET
BT 78.041 248.180 Td /F4 8.7 Tf  [(12)] TJ ET
BT 87.678 248.180 Td /F4 8.7 Tf  [(13)] TJ ET
0.271 0.267 0.267 rg
BT 97.316 246.672 Td /F1 9.8 Tf  [(, use of mechanical devices \(pacemakers, ICDs\))] TJ ET
0.267 0.267 0.267 rg
BT 306.463 248.180 Td /F4 8.7 Tf  [(2)] TJ ET
0.271 0.267 0.267 rg
BT 311.282 246.672 Td /F1 9.8 Tf  [(, and sympathectomy surgery)] TJ ET
0.267 0.267 0.267 rg
BT 439.163 248.180 Td /F4 8.7 Tf  [(4)] TJ ET
0.271 0.267 0.267 rg
BT 443.981 246.672 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 210.070 Td /F4 12.0 Tf  [(Test Description)] TJ ET
BT 26.250 190.116 Td /F1 9.8 Tf  [(Cardiac ion channelopathies result from adverse alterations in genes that code for protein subunits of cardiac ion channels)] TJ ET
0.267 0.267 0.267 rg
BT 553.540 191.623 Td /F4 8.7 Tf  [(1)] TJ ET
0.271 0.267 0.267 rg
BT 558.358 190.116 Td /F1 9.8 Tf  [(. )] TJ ET
BT 26.250 178.211 Td /F1 9.8 Tf  [(The literature differentiates these channelopathies in terms of their subtypes \(e.g., for long QT syndrome, LQT1, LQT2, LQT3, )] TJ ET
BT 26.250 166.306 Td /F1 9.8 Tf  [(LQT4, LQT5, LQT6, �, LQT13\) and the name of the gene affected \(KCNQ1 for LQT1; KCNH2 for LQT2; SCN5A for LQT3; )] TJ ET
BT 26.250 154.401 Td /F1 9.8 Tf  [(ANK2 for LQT4; KCNE1 for LQT5; KCNE2 for LQT6, �, KCNJ5 for LQT13\). Genetic testing is available through a number of )] TJ ET
BT 26.250 142.497 Td /F1 9.8 Tf  [(commercial and university-based genetic diagnostics laboratories)] TJ ET
0.267 0.267 0.267 rg
BT 308.015 144.004 Td /F4 8.7 Tf  [(1)] TJ ET
BT 312.834 144.004 Td /F4 8.7 Tf  [(14)] TJ ET
BT 322.471 144.004 Td /F4 8.7 Tf  [(15)] TJ ET
BT 332.109 144.004 Td /F4 8.7 Tf  [(16)] TJ ET
0.271 0.267 0.267 rg
BT 341.746 142.497 Td /F1 9.8 Tf  [(. Transgenomic \(formerly PGx Health and )] TJ ET
BT 26.250 130.592 Td /F1 9.8 Tf  [(Genaissance\), GeneDx, and Correlagen all offer genetic assays allowing genotyping of LQTS, SQTS, CPVT, and BrS. For )] TJ ET
BT 26.250 118.687 Td /F1 9.8 Tf  [(example, panels offered by Transgenomic)] TJ ET
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BT 207.785 120.194 Td /F4 8.7 Tf  [(17)] TJ ET
0.271 0.267 0.267 rg
BT 217.423 118.687 Td /F1 9.8 Tf  [( and GeneDx)] TJ ET
0.267 0.267 0.267 rg
BT 274.870 120.194 Td /F4 8.7 Tf  [(18)] TJ ET
0.271 0.267 0.267 rg
BT 284.507 118.687 Td /F1 9.8 Tf  [( test for 13 and 12 LQTS genes, respectively, KCNQ1, KCNH2, )] TJ ET
BT 26.250 106.782 Td /F1 9.8 Tf  [(andSCN5A \(LQT1-3\) mutations being most frequent; 3 SQTS genes � mutations in the KCNH2, KCNQ1, andKCNJ2 genes; 4 )] TJ ET
BT 26.250 94.878 Td /F1 9.8 Tf  [(\(Transgenomic\) and 2 \(GeneDx\) CPVT genes, RYR2 mutations being most frequent; and 7 BrS genes, SCN5A mutations being )] TJ ET
BT 26.250 82.973 Td /F1 9.8 Tf  [(most frequent. The Masonic Medical Research Laboratory covers these conditions for research purposes, but specializes in )] TJ ET
BT 26.250 71.068 Td /F1 9.8 Tf  [(acquired as opposed to congenital long QT syndrome)] TJ ET
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BT 257.656 72.575 Td /F4 8.7 Tf  [(19)] TJ ET
0.271 0.267 0.267 rg
BT 267.294 71.068 Td /F1 9.8 Tf  [(. Samples are collected in an EDTA-containing tube; the DNA is )] TJ ET
BT 26.250 59.163 Td /F1 9.8 Tf  [(isolated from fresh whole blood. DNA amplification by polymerase chain reaction \(PCR\) is then used to generate templates for )] TJ ET
BT 26.250 47.259 Td /F1 9.8 Tf  [(direct sequencing. DNA, frozen blood, saliva, and other tissue samples such as buccal specimens have recently been )] TJ ET
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BT 15.000 718.042 Td /F2 21.0 Tf  [(Genetic testing for long QT syndrome and the category of )] TJ ET
BT 15.000 693.094 Td /F2 21.0 Tf  [(cardiac ion channelopathies)] TJ ET
Q
0.271 0.267 0.267 rg
BT 15.000 675.088 Td /F3 9.8 Tf  [(May 3, 2012)] TJ ET
BT 68.888 675.088 Td /F3 9.8 Tf  [(�)] TJ ET
0.267 0.267 0.267 rg
BT 73.763 675.088 Td /F3 9.8 Tf  [(Diagnostic)] TJ ET
BT 26.250 663.247 Td /F1 9.8 Tf  [(Stephen M. Modell)] TJ ET
0.271 0.267 0.267 rg
BT 107.536 663.247 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 112.957 663.247 Td /F1 9.8 Tf  [(David J. Bradley)] TJ ET
0.271 0.267 0.267 rg
BT 183.937 663.247 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 189.358 663.247 Td /F1 9.8 Tf  [(Michael H. Lehmann)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 651.342 Td /F1 9.8 Tf  [(Modell SM, Bradley DJ, Lehmann MH. Genetic testing for long QT syndrome and the category of cardiac ion channelopathies. )] TJ ET
BT 26.250 639.438 Td /F1 9.8 Tf  [(PLOS Currents Evidence on Genomic Tests. 2012 May 3 . Edition 1. doi: 10.1371/4f9995f69e6c7.)] TJ ET
q
15.000 32.973 577.500 604.084 re W n
0.271 0.267 0.267 rg
BT 26.250 610.335 Td /F4 12.0 Tf  [(Abstract)] TJ ET
BT 26.250 590.381 Td /F1 9.8 Tf  [(Cardiac ion channel mutational analysis is a category of genetic testing used in clinical practice for determining the status of )] TJ ET
BT 26.250 578.476 Td /F1 9.8 Tf  [(long QT syndrome, short QT syndrome, catecholaminergic polymorphic ventricular tachycardia, and Brugada syndrome genes )] TJ ET
BT 26.250 566.571 Td /F1 9.8 Tf  [(in blood, saliva, or tissue from patients and family members at risk for cardiac events such as syncope and sudden death. Such )] TJ ET
BT 26.250 554.667 Td /F1 9.8 Tf  [(testing is most informative following careful phenotypic characterization. Individuals with ion channelopathies may benefit from )] TJ ET
BT 26.250 542.762 Td /F1 9.8 Tf  [(prevention \(avoidance of triggers and predisposing drugs\) and treatment \(e.g., beta blocker therapy, implantable cardioverter-)] TJ ET
BT 26.250 530.857 Td /F1 9.8 Tf  [(defibrillator \(ICD\) placement\) modalities.)] TJ ET
BT 26.250 494.255 Td /F4 12.0 Tf  [(Funding Statement)] TJ ET
BT 26.250 474.300 Td /F1 9.8 Tf  [(Funding for this project was made possible by the National Office of Public Health Genomics, Centers for Disease Control and )] TJ ET
BT 26.250 462.396 Td /F1 9.8 Tf  [(Prevention through McKing Consulting Corporation, contract # 200-2009-F-32675.)] TJ ET
BT 26.250 433.293 Td /F4 12.0 Tf  [(Clinical Scenario)] TJ ET
BT 26.250 413.339 Td /F1 9.8 Tf  [(In patients with fainting \(especially occurring during physical exertion or emotional/auditory arousal\), seizures, a history of )] TJ ET
BT 26.250 401.434 Td /F1 9.8 Tf  [(aborted cardiac arrest, a family history of sudden death, or who have themselves succumbed to sudden cardiac death \(SCD\), )] TJ ET
BT 26.250 389.529 Td /F1 9.8 Tf  [(cardiac ion channel mutation testing, typically in conjunction with electrocardiography, can provide important information. )] TJ ET
BT 26.250 377.625 Td /F1 9.8 Tf  [(Performed with cardiac evaluation, genetic testing may be used to determine the status of long QT syndrome \(LQTS\), short QT )] TJ ET
BT 26.250 365.720 Td /F1 9.8 Tf  [(syndrome \(SQTS\), catecholaminergic polymorphic ventricular tachycardia \(CPVT\), and Brugada syndrome \(BrS\) genes from )] TJ ET
BT 26.250 353.815 Td /F1 9.8 Tf  [(blood, saliva, or tissue specimens, including postmortem samples)] TJ ET
0.267 0.267 0.267 rg
BT 309.098 355.322 Td /F4 8.7 Tf  [(1)] TJ ET
BT 313.916 355.322 Td /F4 8.7 Tf  [(2)] TJ ET
BT 318.735 355.322 Td /F4 8.7 Tf  [(3)] TJ ET
0.271 0.267 0.267 rg
BT 323.554 353.815 Td /F1 9.8 Tf  [(. While these conditions demonstrate characteristic )] TJ ET
BT 26.250 341.910 Td /F1 9.8 Tf  [(electrocardiographic patterns \(LQTS � a prolonged QT interval on resting ECG \(part of the Schwartz-Moss diagnostic score\))] TJ ET
0.267 0.267 0.267 rg
BT 561.077 343.418 Td /F4 8.7 Tf  [(4)] TJ ET
0.271 0.267 0.267 rg
BT 565.895 341.910 Td /F1 9.8 Tf  [(; )] TJ ET
BT 26.250 330.006 Td /F1 9.8 Tf  [(CPVT � ventricular ectopy)] TJ ET
0.267 0.267 0.267 rg
BT 139.496 331.513 Td /F4 8.7 Tf  [(5)] TJ ET
0.271 0.267 0.267 rg
BT 144.315 330.006 Td /F1 9.8 Tf  [(; BrS � ST segment elevation)] TJ ET
0.267 0.267 0.267 rg
BT 271.123 331.513 Td /F4 8.7 Tf  [(2)] TJ ET
0.271 0.267 0.267 rg
BT 275.942 330.006 Td /F1 9.8 Tf  [(\), these findings may be absent or inconclusive on a single clinical )] TJ ET
BT 26.250 318.101 Td /F1 9.8 Tf  [(test. Similarly, post-mortem samples may be accompanied by insufficient clinical data for diagnostic classification. Genetic )] TJ ET
BT 26.250 306.196 Td /F1 9.8 Tf  [(testing has been used to exclude one condition over another and to provide definitive diagnosis in many such situations)] TJ ET
0.267 0.267 0.267 rg
BT 540.562 307.703 Td /F4 8.7 Tf  [(1)] TJ ET
BT 545.381 307.703 Td /F4 8.7 Tf  [(6)] TJ ET
BT 550.200 307.703 Td /F4 8.7 Tf  [(7)] TJ ET
0.271 0.267 0.267 rg
BT 555.019 306.196 Td /F1 9.8 Tf  [(. For )] TJ ET
BT 26.250 294.291 Td /F1 9.8 Tf  [(the patient whose symptoms, ECG, and/or other adjunctive tests)] TJ ET
0.267 0.267 0.267 rg
BT 304.252 295.799 Td /F4 8.7 Tf  [(5)] TJ ET
BT 309.070 295.799 Td /F4 8.7 Tf  [(8)] TJ ET
0.271 0.267 0.267 rg
BT 313.889 294.291 Td /F1 9.8 Tf  [( have led to a clinical diagnosis, the test can identify pertinent )] TJ ET
BT 26.250 282.387 Td /F1 9.8 Tf  [(risks and assist management. In addition, relatives of affected patients, who may have no symptoms but are capable of passing )] TJ ET
BT 26.250 270.482 Td /F1 9.8 Tf  [(on an abnormal gene, can be identified through techniques like cascade screening)] TJ ET
0.267 0.267 0.267 rg
BT 381.774 271.989 Td /F4 8.7 Tf  [(1)] TJ ET
BT 386.593 271.989 Td /F4 8.7 Tf  [(3)] TJ ET
BT 391.411 271.989 Td /F4 8.7 Tf  [(6)] TJ ET
BT 396.230 271.989 Td /F4 8.7 Tf  [(9)] TJ ET
0.271 0.267 0.267 rg
BT 401.049 270.482 Td /F1 9.8 Tf  [(. Therapies for patients displaying )] TJ ET
BT 26.250 258.577 Td /F1 9.8 Tf  [(mutations include avoidance of physical triggers and aggravating drugs, placement on anti-arrhythmic drug or beta blocker )] TJ ET
BT 26.250 246.672 Td /F1 9.8 Tf  [(therapy)] TJ ET
0.267 0.267 0.267 rg
BT 58.766 248.180 Td /F4 8.7 Tf  [(10)] TJ ET
BT 68.404 248.180 Td /F4 8.7 Tf  [(11)] TJ ET
BT 78.041 248.180 Td /F4 8.7 Tf  [(12)] TJ ET
BT 87.678 248.180 Td /F4 8.7 Tf  [(13)] TJ ET
0.271 0.267 0.267 rg
BT 97.316 246.672 Td /F1 9.8 Tf  [(, use of mechanical devices \(pacemakers, ICDs\))] TJ ET
0.267 0.267 0.267 rg
BT 306.463 248.180 Td /F4 8.7 Tf  [(2)] TJ ET
0.271 0.267 0.267 rg
BT 311.282 246.672 Td /F1 9.8 Tf  [(, and sympathectomy surgery)] TJ ET
0.267 0.267 0.267 rg
BT 439.163 248.180 Td /F4 8.7 Tf  [(4)] TJ ET
0.271 0.267 0.267 rg
BT 443.981 246.672 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 210.070 Td /F4 12.0 Tf  [(Test Description)] TJ ET
BT 26.250 190.116 Td /F1 9.8 Tf  [(Cardiac ion channelopathies result from adverse alterations in genes that code for protein subunits of cardiac ion channels)] TJ ET
0.267 0.267 0.267 rg
BT 553.540 191.623 Td /F4 8.7 Tf  [(1)] TJ ET
0.271 0.267 0.267 rg
BT 558.358 190.116 Td /F1 9.8 Tf  [(. )] TJ ET
BT 26.250 178.211 Td /F1 9.8 Tf  [(The literature differentiates these channelopathies in terms of their subtypes \(e.g., for long QT syndrome, LQT1, LQT2, LQT3, )] TJ ET
BT 26.250 166.306 Td /F1 9.8 Tf  [(LQT4, LQT5, LQT6, �, LQT13\) and the name of the gene affected \(KCNQ1 for LQT1; KCNH2 for LQT2; SCN5A for LQT3; )] TJ ET
BT 26.250 154.401 Td /F1 9.8 Tf  [(ANK2 for LQT4; KCNE1 for LQT5; KCNE2 for LQT6, �, KCNJ5 for LQT13\). Genetic testing is available through a number of )] TJ ET
BT 26.250 142.497 Td /F1 9.8 Tf  [(commercial and university-based genetic diagnostics laboratories)] TJ ET
0.267 0.267 0.267 rg
BT 308.015 144.004 Td /F4 8.7 Tf  [(1)] TJ ET
BT 312.834 144.004 Td /F4 8.7 Tf  [(14)] TJ ET
BT 322.471 144.004 Td /F4 8.7 Tf  [(15)] TJ ET
BT 332.109 144.004 Td /F4 8.7 Tf  [(16)] TJ ET
0.271 0.267 0.267 rg
BT 341.746 142.497 Td /F1 9.8 Tf  [(. Transgenomic \(formerly PGx Health and )] TJ ET
BT 26.250 130.592 Td /F1 9.8 Tf  [(Genaissance\), GeneDx, and Correlagen all offer genetic assays allowing genotyping of LQTS, SQTS, CPVT, and BrS. For )] TJ ET
BT 26.250 118.687 Td /F1 9.8 Tf  [(example, panels offered by Transgenomic)] TJ ET
0.267 0.267 0.267 rg
BT 207.785 120.194 Td /F4 8.7 Tf  [(17)] TJ ET
0.271 0.267 0.267 rg
BT 217.423 118.687 Td /F1 9.8 Tf  [( and GeneDx)] TJ ET
0.267 0.267 0.267 rg
BT 274.870 120.194 Td /F4 8.7 Tf  [(18)] TJ ET
0.271 0.267 0.267 rg
BT 284.507 118.687 Td /F1 9.8 Tf  [( test for 13 and 12 LQTS genes, respectively, KCNQ1, KCNH2, )] TJ ET
BT 26.250 106.782 Td /F1 9.8 Tf  [(andSCN5A \(LQT1-3\) mutations being most frequent; 3 SQTS genes � mutations in the KCNH2, KCNQ1, andKCNJ2 genes; 4 )] TJ ET
BT 26.250 94.878 Td /F1 9.8 Tf  [(\(Transgenomic\) and 2 \(GeneDx\) CPVT genes, RYR2 mutations being most frequent; and 7 BrS genes, SCN5A mutations being )] TJ ET
BT 26.250 82.973 Td /F1 9.8 Tf  [(most frequent. The Masonic Medical Research Laboratory covers these conditions for research purposes, but specializes in )] TJ ET
BT 26.250 71.068 Td /F1 9.8 Tf  [(acquired as opposed to congenital long QT syndrome)] TJ ET
0.267 0.267 0.267 rg
BT 257.656 72.575 Td /F4 8.7 Tf  [(19)] TJ ET
0.271 0.267 0.267 rg
BT 267.294 71.068 Td /F1 9.8 Tf  [(. Samples are collected in an EDTA-containing tube; the DNA is )] TJ ET
BT 26.250 59.163 Td /F1 9.8 Tf  [(isolated from fresh whole blood. DNA amplification by polymerase chain reaction \(PCR\) is then used to generate templates for )] TJ ET
BT 26.250 47.259 Td /F1 9.8 Tf  [(direct sequencing. DNA, frozen blood, saliva, and other tissue samples such as buccal specimens have recently been )] TJ ET
Q
q
15.000 684.354 577.500 53.646 re W n
0.267 0.267 0.267 rg
BT 15.000 718.042 Td /F2 21.0 Tf  [(Genetic testing for long QT syndrome and the category of )] TJ ET
BT 15.000 693.094 Td /F2 21.0 Tf  [(cardiac ion channelopathies)] TJ ET
Q
0.271 0.267 0.267 rg
BT 15.000 675.088 Td /F3 9.8 Tf  [(May 3, 2012)] TJ ET
BT 68.888 675.088 Td /F3 9.8 Tf  [(�)] TJ ET
0.267 0.267 0.267 rg
BT 73.763 675.088 Td /F3 9.8 Tf  [(Diagnostic)] TJ ET
BT 26.250 663.247 Td /F1 9.8 Tf  [(Stephen M. Modell)] TJ ET
0.271 0.267 0.267 rg
BT 107.536 663.247 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 112.957 663.247 Td /F1 9.8 Tf  [(David J. Bradley)] TJ ET
0.271 0.267 0.267 rg
BT 183.937 663.247 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 189.358 663.247 Td /F1 9.8 Tf  [(Michael H. Lehmann)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 651.342 Td /F1 9.8 Tf  [(Modell SM, Bradley DJ, Lehmann MH. Genetic testing for long QT syndrome and the category of cardiac ion channelopathies. )] TJ ET
BT 26.250 639.438 Td /F1 9.8 Tf  [(PLOS Currents Evidence on Genomic Tests. 2012 May 3 . Edition 1. doi: 10.1371/4f9995f69e6c7.)] TJ ET
q
15.000 32.973 577.500 604.084 re W n
0.271 0.267 0.267 rg
BT 26.250 610.335 Td /F4 12.0 Tf  [(Abstract)] TJ ET
BT 26.250 590.381 Td /F1 9.8 Tf  [(Cardiac ion channel mutational analysis is a category of genetic testing used in clinical practice for determining the status of )] TJ ET
BT 26.250 578.476 Td /F1 9.8 Tf  [(long QT syndrome, short QT syndrome, catecholaminergic polymorphic ventricular tachycardia, and Brugada syndrome genes )] TJ ET
BT 26.250 566.571 Td /F1 9.8 Tf  [(in blood, saliva, or tissue from patients and family members at risk for cardiac events such as syncope and sudden death. Such )] TJ ET
BT 26.250 554.667 Td /F1 9.8 Tf  [(testing is most informative following careful phenotypic characterization. Individuals with ion channelopathies may benefit from )] TJ ET
BT 26.250 542.762 Td /F1 9.8 Tf  [(prevention \(avoidance of triggers and predisposing drugs\) and treatment \(e.g., beta blocker therapy, implantable cardioverter-)] TJ ET
BT 26.250 530.857 Td /F1 9.8 Tf  [(defibrillator \(ICD\) placement\) modalities.)] TJ ET
BT 26.250 494.255 Td /F4 12.0 Tf  [(Funding Statement)] TJ ET
BT 26.250 474.300 Td /F1 9.8 Tf  [(Funding for this project was made possible by the National Office of Public Health Genomics, Centers for Disease Control and )] TJ ET
BT 26.250 462.396 Td /F1 9.8 Tf  [(Prevention through McKing Consulting Corporation, contract # 200-2009-F-32675.)] TJ ET
BT 26.250 433.293 Td /F4 12.0 Tf  [(Clinical Scenario)] TJ ET
BT 26.250 413.339 Td /F1 9.8 Tf  [(In patients with fainting \(especially occurring during physical exertion or emotional/auditory arousal\), seizures, a history of )] TJ ET
BT 26.250 401.434 Td /F1 9.8 Tf  [(aborted cardiac arrest, a family history of sudden death, or who have themselves succumbed to sudden cardiac death \(SCD\), )] TJ ET
BT 26.250 389.529 Td /F1 9.8 Tf  [(cardiac ion channel mutation testing, typically in conjunction with electrocardiography, can provide important information. )] TJ ET
BT 26.250 377.625 Td /F1 9.8 Tf  [(Performed with cardiac evaluation, genetic testing may be used to determine the status of long QT syndrome \(LQTS\), short QT )] TJ ET
BT 26.250 365.720 Td /F1 9.8 Tf  [(syndrome \(SQTS\), catecholaminergic polymorphic ventricular tachycardia \(CPVT\), and Brugada syndrome \(BrS\) genes from )] TJ ET
BT 26.250 353.815 Td /F1 9.8 Tf  [(blood, saliva, or tissue specimens, including postmortem samples)] TJ ET
0.267 0.267 0.267 rg
BT 309.098 355.322 Td /F4 8.7 Tf  [(1)] TJ ET
BT 313.916 355.322 Td /F4 8.7 Tf  [(2)] TJ ET
BT 318.735 355.322 Td /F4 8.7 Tf  [(3)] TJ ET
0.271 0.267 0.267 rg
BT 323.554 353.815 Td /F1 9.8 Tf  [(. While these conditions demonstrate characteristic )] TJ ET
BT 26.250 341.910 Td /F1 9.8 Tf  [(electrocardiographic patterns \(LQTS � a prolonged QT interval on resting ECG \(part of the Schwartz-Moss diagnostic score\))] TJ ET
0.267 0.267 0.267 rg
BT 561.077 343.418 Td /F4 8.7 Tf  [(4)] TJ ET
0.271 0.267 0.267 rg
BT 565.895 341.910 Td /F1 9.8 Tf  [(; )] TJ ET
BT 26.250 330.006 Td /F1 9.8 Tf  [(CPVT � ventricular ectopy)] TJ ET
0.267 0.267 0.267 rg
BT 139.496 331.513 Td /F4 8.7 Tf  [(5)] TJ ET
0.271 0.267 0.267 rg
BT 144.315 330.006 Td /F1 9.8 Tf  [(; BrS � ST segment elevation)] TJ ET
0.267 0.267 0.267 rg
BT 271.123 331.513 Td /F4 8.7 Tf  [(2)] TJ ET
0.271 0.267 0.267 rg
BT 275.942 330.006 Td /F1 9.8 Tf  [(\), these findings may be absent or inconclusive on a single clinical )] TJ ET
BT 26.250 318.101 Td /F1 9.8 Tf  [(test. Similarly, post-mortem samples may be accompanied by insufficient clinical data for diagnostic classification. Genetic )] TJ ET
BT 26.250 306.196 Td /F1 9.8 Tf  [(testing has been used to exclude one condition over another and to provide definitive diagnosis in many such situations)] TJ ET
0.267 0.267 0.267 rg
BT 540.562 307.703 Td /F4 8.7 Tf  [(1)] TJ ET
BT 545.381 307.703 Td /F4 8.7 Tf  [(6)] TJ ET
BT 550.200 307.703 Td /F4 8.7 Tf  [(7)] TJ ET
0.271 0.267 0.267 rg
BT 555.019 306.196 Td /F1 9.8 Tf  [(. For )] TJ ET
BT 26.250 294.291 Td /F1 9.8 Tf  [(the patient whose symptoms, ECG, and/or other adjunctive tests)] TJ ET
0.267 0.267 0.267 rg
BT 304.252 295.799 Td /F4 8.7 Tf  [(5)] TJ ET
BT 309.070 295.799 Td /F4 8.7 Tf  [(8)] TJ ET
0.271 0.267 0.267 rg
BT 313.889 294.291 Td /F1 9.8 Tf  [( have led to a clinical diagnosis, the test can identify pertinent )] TJ ET
BT 26.250 282.387 Td /F1 9.8 Tf  [(risks and assist management. In addition, relatives of affected patients, who may have no symptoms but are capable of passing )] TJ ET
BT 26.250 270.482 Td /F1 9.8 Tf  [(on an abnormal gene, can be identified through techniques like cascade screening)] TJ ET
0.267 0.267 0.267 rg
BT 381.774 271.989 Td /F4 8.7 Tf  [(1)] TJ ET
BT 386.593 271.989 Td /F4 8.7 Tf  [(3)] TJ ET
BT 391.411 271.989 Td /F4 8.7 Tf  [(6)] TJ ET
BT 396.230 271.989 Td /F4 8.7 Tf  [(9)] TJ ET
0.271 0.267 0.267 rg
BT 401.049 270.482 Td /F1 9.8 Tf  [(. Therapies for patients displaying )] TJ ET
BT 26.250 258.577 Td /F1 9.8 Tf  [(mutations include avoidance of physical triggers and aggravating drugs, placement on anti-arrhythmic drug or beta blocker )] TJ ET
BT 26.250 246.672 Td /F1 9.8 Tf  [(therapy)] TJ ET
0.267 0.267 0.267 rg
BT 58.766 248.180 Td /F4 8.7 Tf  [(10)] TJ ET
BT 68.404 248.180 Td /F4 8.7 Tf  [(11)] TJ ET
BT 78.041 248.180 Td /F4 8.7 Tf  [(12)] TJ ET
BT 87.678 248.180 Td /F4 8.7 Tf  [(13)] TJ ET
0.271 0.267 0.267 rg
BT 97.316 246.672 Td /F1 9.8 Tf  [(, use of mechanical devices \(pacemakers, ICDs\))] TJ ET
0.267 0.267 0.267 rg
BT 306.463 248.180 Td /F4 8.7 Tf  [(2)] TJ ET
0.271 0.267 0.267 rg
BT 311.282 246.672 Td /F1 9.8 Tf  [(, and sympathectomy surgery)] TJ ET
0.267 0.267 0.267 rg
BT 439.163 248.180 Td /F4 8.7 Tf  [(4)] TJ ET
0.271 0.267 0.267 rg
BT 443.981 246.672 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 210.070 Td /F4 12.0 Tf  [(Test Description)] TJ ET
BT 26.250 190.116 Td /F1 9.8 Tf  [(Cardiac ion channelopathies result from adverse alterations in genes that code for protein subunits of cardiac ion channels)] TJ ET
0.267 0.267 0.267 rg
BT 553.540 191.623 Td /F4 8.7 Tf  [(1)] TJ ET
0.271 0.267 0.267 rg
BT 558.358 190.116 Td /F1 9.8 Tf  [(. )] TJ ET
BT 26.250 178.211 Td /F1 9.8 Tf  [(The literature differentiates these channelopathies in terms of their subtypes \(e.g., for long QT syndrome, LQT1, LQT2, LQT3, )] TJ ET
BT 26.250 166.306 Td /F1 9.8 Tf  [(LQT4, LQT5, LQT6, �, LQT13\) and the name of the gene affected \(KCNQ1 for LQT1; KCNH2 for LQT2; SCN5A for LQT3; )] TJ ET
BT 26.250 154.401 Td /F1 9.8 Tf  [(ANK2 for LQT4; KCNE1 for LQT5; KCNE2 for LQT6, �, KCNJ5 for LQT13\). Genetic testing is available through a number of )] TJ ET
BT 26.250 142.497 Td /F1 9.8 Tf  [(commercial and university-based genetic diagnostics laboratories)] TJ ET
0.267 0.267 0.267 rg
BT 308.015 144.004 Td /F4 8.7 Tf  [(1)] TJ ET
BT 312.834 144.004 Td /F4 8.7 Tf  [(14)] TJ ET
BT 322.471 144.004 Td /F4 8.7 Tf  [(15)] TJ ET
BT 332.109 144.004 Td /F4 8.7 Tf  [(16)] TJ ET
0.271 0.267 0.267 rg
BT 341.746 142.497 Td /F1 9.8 Tf  [(. Transgenomic \(formerly PGx Health and )] TJ ET
BT 26.250 130.592 Td /F1 9.8 Tf  [(Genaissance\), GeneDx, and Correlagen all offer genetic assays allowing genotyping of LQTS, SQTS, CPVT, and BrS. For )] TJ ET
BT 26.250 118.687 Td /F1 9.8 Tf  [(example, panels offered by Transgenomic)] TJ ET
0.267 0.267 0.267 rg
BT 207.785 120.194 Td /F4 8.7 Tf  [(17)] TJ ET
0.271 0.267 0.267 rg
BT 217.423 118.687 Td /F1 9.8 Tf  [( and GeneDx)] TJ ET
0.267 0.267 0.267 rg
BT 274.870 120.194 Td /F4 8.7 Tf  [(18)] TJ ET
0.271 0.267 0.267 rg
BT 284.507 118.687 Td /F1 9.8 Tf  [( test for 13 and 12 LQTS genes, respectively, KCNQ1, KCNH2, )] TJ ET
BT 26.250 106.782 Td /F1 9.8 Tf  [(andSCN5A \(LQT1-3\) mutations being most frequent; 3 SQTS genes � mutations in the KCNH2, KCNQ1, andKCNJ2 genes; 4 )] TJ ET
BT 26.250 94.878 Td /F1 9.8 Tf  [(\(Transgenomic\) and 2 \(GeneDx\) CPVT genes, RYR2 mutations being most frequent; and 7 BrS genes, SCN5A mutations being )] TJ ET
BT 26.250 82.973 Td /F1 9.8 Tf  [(most frequent. The Masonic Medical Research Laboratory covers these conditions for research purposes, but specializes in )] TJ ET
BT 26.250 71.068 Td /F1 9.8 Tf  [(acquired as opposed to congenital long QT syndrome)] TJ ET
0.267 0.267 0.267 rg
BT 257.656 72.575 Td /F4 8.7 Tf  [(19)] TJ ET
0.271 0.267 0.267 rg
BT 267.294 71.068 Td /F1 9.8 Tf  [(. Samples are collected in an EDTA-containing tube; the DNA is )] TJ ET
BT 26.250 59.163 Td /F1 9.8 Tf  [(isolated from fresh whole blood. DNA amplification by polymerase chain reaction \(PCR\) is then used to generate templates for )] TJ ET
BT 26.250 47.259 Td /F1 9.8 Tf  [(direct sequencing. DNA, frozen blood, saliva, and other tissue samples such as buccal specimens have recently been )] TJ ET
Q
q
0.000 0.000 0.000 rg
BT 291.710 19.825 Td /F1 11.0 Tf  [(1)] TJ ET
BT 25.000 19.825 Td /F1 11.0 Tf  [(PLOS Currents Evidence on Genomic Tests)] TJ ET

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BT 26.250 767.476 Td /F1 9.8 Tf  [(accommodated by some labs)] TJ ET
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BT 153.049 768.983 Td /F4 8.7 Tf  [(17)] TJ ET
BT 162.686 768.983 Td /F4 8.7 Tf  [(18)] TJ ET
0.271 0.267 0.267 rg
BT 172.323 767.476 Td /F1 9.8 Tf  [(. Detailed results are provided for each test panel, typically with a description of known )] TJ ET
BT 26.250 755.571 Td /F1 9.8 Tf  [(literature on any identified mutation and its likelihood to cause disease. Focused testing for a single mutation relevant to a )] TJ ET
BT 26.250 743.667 Td /F1 9.8 Tf  [(patient�s family, rather than a panel of potentially involved genes, is available at a lower cost.)] TJ ET
BT 26.250 707.064 Td /F4 12.0 Tf  [(Public Health Importance)] TJ ET
BT 26.250 687.110 Td /F1 9.8 Tf  [(The public health importance of these inherited arrhythmia syndromes is highlighted by their potential lethality, mostly due to )] TJ ET
BT 26.250 675.205 Td /F1 9.8 Tf  [(ventricular tachyarrhythmias)] TJ ET
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BT 148.154 676.712 Td /F4 8.7 Tf  [(20)] TJ ET
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BT 157.792 675.205 Td /F1 9.8 Tf  [(. Long QT syndrome may be responsible for as many as 3,000 unexpected deaths in children )] TJ ET
BT 26.250 663.300 Td /F1 9.8 Tf  [(and young adults annually in the United States)] TJ ET
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BT 227.324 664.808 Td /F4 8.7 Tf  [(21)] TJ ET
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BT 236.962 663.300 Td /F1 9.8 Tf  [(. Catecholaminergic polymorphic ventricular tachycardia carries a high )] TJ ET
BT 26.250 651.396 Td /F1 9.8 Tf  [(mortality in untreated cases)] TJ ET
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BT 145.463 652.903 Td /F4 8.7 Tf  [(5)] TJ ET
BT 150.282 652.903 Td /F4 8.7 Tf  [(7)] TJ ET
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BT 155.101 651.396 Td /F1 9.8 Tf  [(. The current state of technology, however, does not enable arrhythmia screening of broad, )] TJ ET
BT 26.250 639.491 Td /F1 9.8 Tf  [(potentially at-risk populations � athletes, all children, all patients exposed to QT-prolonging drugs, or all patients with a history of )] TJ ET
BT 26.250 627.586 Td /F1 9.8 Tf  [(syncope)] TJ ET
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BT 62.559 629.093 Td /F4 8.7 Tf  [(6)] TJ ET
BT 67.378 629.093 Td /F4 8.7 Tf  [(16)] TJ ET
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BT 77.015 627.586 Td /F1 9.8 Tf  [(. Subpopulations of sudden death victims are of great interest. It is estimated that approximately 25-35% of autopsy-)] TJ ET
BT 26.250 615.681 Td /F1 9.8 Tf  [(negative or unexplained sudden cardiac death in the young, and 10% of sudden infant death \(SIDS\) may be attributable to )] TJ ET
BT 26.250 603.777 Td /F1 9.8 Tf  [(mutations in either LQTS or CPVT susceptibility genes)] TJ ET
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BT 261.420 605.284 Td /F4 8.7 Tf  [(22)] TJ ET
0.271 0.267 0.267 rg
BT 271.057 603.777 Td /F1 9.8 Tf  [(. Brugada syndrome may be responsible for 4-15% of unexpected )] TJ ET
BT 26.250 591.872 Td /F1 9.8 Tf  [(sudden deaths, particularly in individuals with an apparently normal heart)] TJ ET
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BT 340.551 593.379 Td /F4 8.7 Tf  [(23)] TJ ET
BT 350.188 593.379 Td /F4 8.7 Tf  [(24)] TJ ET
BT 359.826 593.379 Td /F4 8.7 Tf  [(25)] TJ ET
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BT 369.463 591.872 Td /F1 9.8 Tf  [(.)] TJ ET
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BT 26.250 571.002 Td /F1 9.8 Tf  [(Table of Cardiac Ion Channelopathies)] TJ ET
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0.267 0.267 0.267 rg
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0.965 0.965 0.965 rg
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117.580 559.630 92.851 0.750 re f
0.271 0.267 0.267 rg
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BT 122.080 538.576 Td /F4 9.8 Tf  [(syndrome )] TJ ET
BT 122.080 526.671 Td /F4 9.8 Tf  [(\(LQTS\) )] TJ ET
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BT 157.288 526.671 Td /F4 8.7 Tf  [(17)] TJ ET
BT 166.925 526.671 Td /F4 8.7 Tf  [(26)] TJ ET
BT 176.562 526.671 Td /F4 8.7 Tf  [(27)] TJ ET
BT 186.200 526.671 Td /F4 8.7 Tf  [(28)] TJ ET
BT 195.837 526.671 Td /F4 8.7 Tf  [(75)] TJ ET
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0.267 0.267 0.267 rg
210.431 559.630 96.248 0.750 re f
0.271 0.267 0.267 rg
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BT 214.931 527.730 Td /F4 8.7 Tf  [(17)] TJ ET
BT 224.569 527.730 Td /F4 8.7 Tf  [(18)] TJ ET
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306.679 559.630 164.601 0.750 re f
0.271 0.267 0.267 rg
BT 311.179 550.481 Td /F4 9.8 Tf  [(Catecholaminergic polymorphic )] TJ ET
BT 311.179 538.576 Td /F4 9.8 Tf  [(ventricular tachycardia \(CPVT\) )] TJ ET
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BT 455.850 538.576 Td /F4 8.7 Tf  [(5)] TJ ET
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BT 320.817 527.730 Td /F4 8.7 Tf  [(30)] TJ ET
BT 330.454 527.730 Td /F4 8.7 Tf  [(31)] TJ ET
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0.267 0.267 0.267 rg
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580.125 523.540 0.750 36.839 re f
0.271 0.267 0.267 rg
BT 475.781 550.481 Td /F4 9.8 Tf  [(Brugada syndrome )] TJ ET
BT 475.781 538.576 Td /F4 9.8 Tf  [(\(BrS\) )] TJ ET
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BT 502.320 538.576 Td /F4 8.7 Tf  [(17)] TJ ET
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BT 521.595 538.576 Td /F4 8.7 Tf  [(33)] TJ ET
BT 531.232 538.576 Td /F4 8.7 Tf  [(34)] TJ ET
BT 540.870 538.576 Td /F4 8.7 Tf  [(35)] TJ ET
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0.271 0.267 0.267 rg
BT 31.875 513.685 Td /F1 9.8 Tf  [(Prevalence)] TJ ET
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0.271 0.267 0.267 rg
BT 122.455 513.685 Td /F1 9.8 Tf  [(1:5,000 to 1:2,000)] TJ ET
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210.056 523.540 96.998 0.750 re f
210.056 484.765 0.750 39.525 re f
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BT 215.306 513.685 Td /F1 9.8 Tf  [(Rare � fewer than )] TJ ET
BT 215.306 506.054 Td /F1 9.8 Tf  [(30 cases published)] TJ ET
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0.271 0.267 0.267 rg
BT 311.554 513.685 Td /F1 9.8 Tf  [(1:7,000 to 1:10,000)] TJ ET
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580.125 484.765 0.750 39.525 re f
0.271 0.267 0.267 rg
BT 476.156 513.685 Td /F1 9.8 Tf  [(1:800 \(Japan\); )] TJ ET
BT 476.156 506.054 Td /F1 9.8 Tf  [(1:6,000 \(U.S. & )] TJ ET
BT 476.156 498.423 Td /F1 9.8 Tf  [(Europe\) type 1 ECG )] TJ ET
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BT 31.875 474.910 Td /F1 9.8 Tf  [(Annual mortality )] TJ ET
BT 31.875 467.279 Td /F1 9.8 Tf  [(rate)] TJ ET
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117.205 484.765 93.601 0.750 re f
117.205 453.622 0.750 31.894 re f
0.271 0.267 0.267 rg
BT 122.455 474.910 Td /F1 9.8 Tf  [(0.3% \(LQT1\))] TJ ET
BT 122.455 467.279 Td /F1 9.8 Tf  [(0.6% \(LQT2\))] TJ ET
BT 122.455 459.648 Td /F1 9.8 Tf  [(0.56% \(LQT3\))] TJ ET
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210.056 484.765 96.998 0.750 re f
210.056 453.622 0.750 31.894 re f
0.271 0.267 0.267 rg
BT 215.306 474.910 Td /F1 9.8 Tf  [(Unidentified)] TJ ET
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306.304 453.622 0.750 31.894 re f
0.271 0.267 0.267 rg
BT 311.554 474.910 Td /F1 9.8 Tf  [(3.1%)] TJ ET
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BT 476.156 474.910 Td /F1 9.8 Tf  [(4% \(pts. with type 1 )] TJ ET
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0.271 0.267 0.267 rg
BT 31.875 443.767 Td /F1 9.8 Tf  [(Mean age of first )] TJ ET
BT 31.875 436.135 Td /F1 9.8 Tf  [(event)] TJ ET
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117.205 430.109 0.750 24.263 re f
0.271 0.267 0.267 rg
BT 122.455 443.767 Td /F1 9.8 Tf  [(14 � 12 yrs.)] TJ ET
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210.056 430.109 0.750 24.263 re f
0.271 0.267 0.267 rg
BT 215.306 443.767 Td /F1 9.8 Tf  [(40 � 24 yrs.)] TJ ET
0.267 0.267 0.267 rg
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306.304 430.109 0.750 24.263 re f
0.271 0.267 0.267 rg
BT 311.554 443.767 Td /F1 9.8 Tf  [(15 � 10 yrs.)] TJ ET
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470.906 430.109 0.750 24.263 re f
580.125 430.109 0.750 24.263 re f
0.271 0.267 0.267 rg
BT 476.156 443.767 Td /F1 9.8 Tf  [(42 � 16 yrs. \(pts. with )] TJ ET
BT 476.156 436.135 Td /F1 9.8 Tf  [(type 1 ECG\))] TJ ET
0.267 0.267 0.267 rg
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26.625 406.597 91.330 0.750 re f
26.625 406.597 0.750 24.263 re f
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BT 31.875 420.254 Td /F1 9.8 Tf  [(Diagnostic Yield � )] TJ ET
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117.205 406.597 93.601 0.750 re f
117.205 406.597 0.750 24.263 re f
0.271 0.267 0.267 rg
BT 122.455 420.254 Td /F1 9.8 Tf  [(75-80%)] TJ ET
0.267 0.267 0.267 rg
210.056 430.109 96.998 0.750 re f
210.056 406.597 96.998 0.750 re f
210.056 406.597 0.750 24.263 re f
0.271 0.267 0.267 rg
BT 215.306 420.254 Td /F1 9.8 Tf  [(15-20%)] TJ ET
0.267 0.267 0.267 rg
306.304 430.109 165.351 0.750 re f
306.304 406.597 165.351 0.750 re f
306.304 406.597 0.750 24.263 re f
0.271 0.267 0.267 rg
BT 311.554 420.254 Td /F1 9.8 Tf  [(65-75%)] TJ ET
0.267 0.267 0.267 rg
470.906 430.109 109.969 0.750 re f
470.906 406.597 109.969 0.750 re f
470.906 406.597 0.750 24.263 re f
580.125 406.597 0.750 24.263 re f
0.271 0.267 0.267 rg
BT 476.156 420.254 Td /F1 9.8 Tf  [(11-40% \(see Clinical )] TJ ET
BT 476.156 412.623 Td /F1 9.8 Tf  [(Validity\))] TJ ET
BT 26.250 351.698 Td /F1 9.8 Tf  [(In the case of LQTS, the specific genotype has prognostic value)] TJ ET
0.267 0.267 0.267 rg
BT 302.107 353.205 Td /F4 8.7 Tf  [(1)] TJ ET
BT 306.925 353.205 Td /F4 8.7 Tf  [(6)] TJ ET
0.271 0.267 0.267 rg
BT 311.744 351.698 Td /F1 9.8 Tf  [(. In studies ranging from 250 to 300,000 genotyped )] TJ ET
BT 26.250 339.793 Td /F1 9.8 Tf  [(individuals through age 60 drawn from the International LQTS Registry, the LQT3 genotype has demonstrated a 5- to 8-fold )] TJ ET
BT 26.250 327.888 Td /F1 9.8 Tf  [(higher risk for life-threatening events compared to the LQT1 and 2 genotypes)] TJ ET
0.267 0.267 0.267 rg
BT 358.998 329.396 Td /F4 8.7 Tf  [(36)] TJ ET
0.271 0.267 0.267 rg
BT 368.635 327.888 Td /F1 9.8 Tf  [(. The LQT2 genotype displays a risk )] TJ ET
BT 26.250 315.984 Td /F1 9.8 Tf  [(intermediate between LQT1 and LQT3)] TJ ET
0.267 0.267 0.267 rg
BT 192.624 317.491 Td /F4 8.7 Tf  [(36)] TJ ET
0.271 0.267 0.267 rg
BT 202.261 315.984 Td /F1 9.8 Tf  [(, though the statistical strength and ordering of this relationship depends on age, sex, )] TJ ET
BT 26.250 304.079 Td /F1 9.8 Tf  [(and source of the cohort)] TJ ET
0.267 0.267 0.267 rg
BT 131.394 305.586 Td /F4 8.7 Tf  [(10)] TJ ET
BT 141.031 305.586 Td /F4 8.7 Tf  [(37)] TJ ET
0.271 0.267 0.267 rg
BT 150.669 304.079 Td /F1 9.8 Tf  [(. Subgroup analyses have more precisely defined the impact of QTc duration and genotype in )] TJ ET
BT 26.250 292.174 Td /F1 9.8 Tf  [(children and adolescents with LQT1 and 2)] TJ ET
0.267 0.267 0.267 rg
BT 208.341 293.681 Td /F4 8.7 Tf  [(38)] TJ ET
0.271 0.267 0.267 rg
BT 217.978 292.174 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 255.572 Td /F4 12.0 Tf  [(Published Reviews, Recommendations and Guidelines)] TJ ET
BT 26.250 235.617 Td /F5 9.8 Tf  [(Systematic evidence reviews)] TJ ET
BT 26.250 216.213 Td /F1 9.8 Tf  [(The Hayes Inc. Genetic Test Evaluation \(GTE\) Program has prepared three evaluations of ion channelopathies: long QT )] TJ ET
BT 26.250 204.308 Td /F1 9.8 Tf  [(syndrome, CPVT, and Brugada syndrome. These reviews were based on studies of primary literature retrieved from PUBMED )] TJ ET
BT 26.250 192.403 Td /F1 9.8 Tf  [(and Embase in the following date ranges: LQTS � January 1, 1996 to June 16, 2009; CPVT � January 1, 1996 to February 10, )] TJ ET
BT 26.250 180.498 Td /F1 9.8 Tf  [(2010; and Brugada syndrome � January 1, 1996 to August 3, 2010)] TJ ET
0.267 0.267 0.267 rg
BT 314.596 182.006 Td /F4 8.7 Tf  [(39)] TJ ET
0.271 0.267 0.267 rg
BT 324.234 180.498 Td /F1 9.8 Tf  [(. DNA Direct, Inc. has published two systematic reviews of )] TJ ET
BT 26.250 168.594 Td /F1 9.8 Tf  [(LQTS genetic testing through its Genomic Medicine Institute. The reviews, which the company makes available with interactive )] TJ ET
BT 26.250 156.689 Td /F1 9.8 Tf  [(tools and decision support, are based on studies of primary patient data published between 2001 and 2008)] TJ ET
0.267 0.267 0.267 rg
BT 486.928 158.196 Td /F4 8.7 Tf  [(40)] TJ ET
0.271 0.267 0.267 rg
BT 496.565 156.689 Td /F1 9.8 Tf  [(. BlueCross )] TJ ET
BT 26.250 144.784 Td /F1 9.8 Tf  [(BlueShield Association and Kaiser Permanente published a systematic review of genetic testing for long QT syndrome through )] TJ ET
BT 26.250 132.879 Td /F1 9.8 Tf  [(the BlueCross BlueShield Technology Evaluation Center \(BCBS Tec\))] TJ ET
0.267 0.267 0.267 rg
BT 324.824 134.387 Td /F4 8.7 Tf  [(41)] TJ ET
0.271 0.267 0.267 rg
BT 334.462 132.879 Td /F1 9.8 Tf  [(. The review was based on studies of primary patient )] TJ ET
BT 26.250 120.975 Td /F1 9.8 Tf  [(data appearing in Medline and PUBMED published between 1990 and October 2007. The Australia and New Zealand Horizon )] TJ ET
BT 26.250 109.070 Td /F1 9.8 Tf  [(Scanning Network released a Horizon Scanning Report on genetic testing for congenital long QT syndrome based principally on )] TJ ET
BT 26.250 97.165 Td /F1 9.8 Tf  [(nine peer-reviewed articles, and detailing safety \(e.g., false negatives\), effectiveness, clinical utility \(cost-effectiveness\), and )] TJ ET
BT 26.250 85.260 Td /F1 9.8 Tf  [(ethical \(consent and privacy, harms from testing, access\) considerations)] TJ ET
0.267 0.267 0.267 rg
BT 337.821 86.768 Td /F4 8.7 Tf  [(42)] TJ ET
0.271 0.267 0.267 rg
BT 347.458 85.260 Td /F1 9.8 Tf  [(. Investigative teams have published comprehensive )] TJ ET
BT 26.250 73.356 Td /F1 9.8 Tf  [(clinical-epidemiologic reviews of both long QT syndrome as a family and several of the other channelopathies under Human )] TJ ET
BT 26.250 61.451 Td /F1 9.8 Tf  [(Genome Epidemiology \(HuGE\) reviews \(e.g., long QT syndrome)] TJ ET
0.267 0.267 0.267 rg
BT 304.213 62.958 Td /F4 8.7 Tf  [(21)] TJ ET
0.271 0.267 0.267 rg
BT 313.850 61.451 Td /F1 9.8 Tf  [(\) and GeneReviews \(e.g., Brugada syndrome)] TJ ET
0.267 0.267 0.267 rg
BT 509.474 62.958 Td /F4 8.7 Tf  [(43)] TJ ET
0.271 0.267 0.267 rg
BT 519.111 61.451 Td /F1 9.8 Tf  [(\).)] TJ ET
Q
q
15.000 32.165 577.500 744.835 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F1 9.8 Tf  [(accommodated by some labs)] TJ ET
0.267 0.267 0.267 rg
BT 153.049 768.983 Td /F4 8.7 Tf  [(17)] TJ ET
BT 162.686 768.983 Td /F4 8.7 Tf  [(18)] TJ ET
0.271 0.267 0.267 rg
BT 172.323 767.476 Td /F1 9.8 Tf  [(. Detailed results are provided for each test panel, typically with a description of known )] TJ ET
BT 26.250 755.571 Td /F1 9.8 Tf  [(literature on any identified mutation and its likelihood to cause disease. Focused testing for a single mutation relevant to a )] TJ ET
BT 26.250 743.667 Td /F1 9.8 Tf  [(patient�s family, rather than a panel of potentially involved genes, is available at a lower cost.)] TJ ET
BT 26.250 707.064 Td /F4 12.0 Tf  [(Public Health Importance)] TJ ET
BT 26.250 687.110 Td /F1 9.8 Tf  [(The public health importance of these inherited arrhythmia syndromes is highlighted by their potential lethality, mostly due to )] TJ ET
BT 26.250 675.205 Td /F1 9.8 Tf  [(ventricular tachyarrhythmias)] TJ ET
0.267 0.267 0.267 rg
BT 148.154 676.712 Td /F4 8.7 Tf  [(20)] TJ ET
0.271 0.267 0.267 rg
BT 157.792 675.205 Td /F1 9.8 Tf  [(. Long QT syndrome may be responsible for as many as 3,000 unexpected deaths in children )] TJ ET
BT 26.250 663.300 Td /F1 9.8 Tf  [(and young adults annually in the United States)] TJ ET
0.267 0.267 0.267 rg
BT 227.324 664.808 Td /F4 8.7 Tf  [(21)] TJ ET
0.271 0.267 0.267 rg
BT 236.962 663.300 Td /F1 9.8 Tf  [(. Catecholaminergic polymorphic ventricular tachycardia carries a high )] TJ ET
BT 26.250 651.396 Td /F1 9.8 Tf  [(mortality in untreated cases)] TJ ET
0.267 0.267 0.267 rg
BT 145.463 652.903 Td /F4 8.7 Tf  [(5)] TJ ET
BT 150.282 652.903 Td /F4 8.7 Tf  [(7)] TJ ET
0.271 0.267 0.267 rg
BT 155.101 651.396 Td /F1 9.8 Tf  [(. The current state of technology, however, does not enable arrhythmia screening of broad, )] TJ ET
BT 26.250 639.491 Td /F1 9.8 Tf  [(potentially at-risk populations � athletes, all children, all patients exposed to QT-prolonging drugs, or all patients with a history of )] TJ ET
BT 26.250 627.586 Td /F1 9.8 Tf  [(syncope)] TJ ET
0.267 0.267 0.267 rg
BT 62.559 629.093 Td /F4 8.7 Tf  [(6)] TJ ET
BT 67.378 629.093 Td /F4 8.7 Tf  [(16)] TJ ET
0.271 0.267 0.267 rg
BT 77.015 627.586 Td /F1 9.8 Tf  [(. Subpopulations of sudden death victims are of great interest. It is estimated that approximately 25-35% of autopsy-)] TJ ET
BT 26.250 615.681 Td /F1 9.8 Tf  [(negative or unexplained sudden cardiac death in the young, and 10% of sudden infant death \(SIDS\) may be attributable to )] TJ ET
BT 26.250 603.777 Td /F1 9.8 Tf  [(mutations in either LQTS or CPVT susceptibility genes)] TJ ET
0.267 0.267 0.267 rg
BT 261.420 605.284 Td /F4 8.7 Tf  [(22)] TJ ET
0.271 0.267 0.267 rg
BT 271.057 603.777 Td /F1 9.8 Tf  [(. Brugada syndrome may be responsible for 4-15% of unexpected )] TJ ET
BT 26.250 591.872 Td /F1 9.8 Tf  [(sudden deaths, particularly in individuals with an apparently normal heart)] TJ ET
0.267 0.267 0.267 rg
BT 340.551 593.379 Td /F4 8.7 Tf  [(23)] TJ ET
BT 350.188 593.379 Td /F4 8.7 Tf  [(24)] TJ ET
BT 359.826 593.379 Td /F4 8.7 Tf  [(25)] TJ ET
0.271 0.267 0.267 rg
BT 369.463 591.872 Td /F1 9.8 Tf  [(.)] TJ ET
q
26.250 568.255 555.000 13.736 re W n
0.271 0.267 0.267 rg
BT 26.250 571.002 Td /F1 9.8 Tf  [(Table of Cardiac Ion Channelopathies)] TJ ET
Q
1.000 1.000 1.000 rg
26.250 406.222 555.000 154.533 re f
0.965 0.965 0.965 rg
27.000 523.915 90.580 36.089 re f
0.267 0.267 0.267 rg
26.625 559.630 90.955 0.750 re f
26.625 523.540 0.750 36.839 re f
0.965 0.965 0.965 rg
117.580 523.915 92.851 36.089 re f
0.267 0.267 0.267 rg
117.580 559.630 92.851 0.750 re f
0.271 0.267 0.267 rg
BT 122.080 550.481 Td /F4 9.8 Tf  [(Long QT )] TJ ET
BT 122.080 538.576 Td /F4 9.8 Tf  [(syndrome )] TJ ET
BT 122.080 526.671 Td /F4 9.8 Tf  [(\(LQTS\) )] TJ ET
0.267 0.267 0.267 rg
BT 157.288 526.671 Td /F4 8.7 Tf  [(17)] TJ ET
BT 166.925 526.671 Td /F4 8.7 Tf  [(26)] TJ ET
BT 176.562 526.671 Td /F4 8.7 Tf  [(27)] TJ ET
BT 186.200 526.671 Td /F4 8.7 Tf  [(28)] TJ ET
BT 195.837 526.671 Td /F4 8.7 Tf  [(75)] TJ ET
0.965 0.965 0.965 rg
210.431 523.915 96.248 36.089 re f
0.267 0.267 0.267 rg
210.431 559.630 96.248 0.750 re f
0.271 0.267 0.267 rg
BT 214.931 550.481 Td /F4 9.8 Tf  [(Short QT )] TJ ET
BT 214.931 538.576 Td /F4 9.8 Tf  [(syndrome \(SQTS\) )] TJ ET
0.267 0.267 0.267 rg
BT 214.931 527.730 Td /F4 8.7 Tf  [(17)] TJ ET
BT 224.569 527.730 Td /F4 8.7 Tf  [(18)] TJ ET
BT 234.206 527.730 Td /F4 8.7 Tf  [(29)] TJ ET
0.965 0.965 0.965 rg
306.679 523.915 164.601 36.089 re f
0.267 0.267 0.267 rg
306.679 559.630 164.601 0.750 re f
0.271 0.267 0.267 rg
BT 311.179 550.481 Td /F4 9.8 Tf  [(Catecholaminergic polymorphic )] TJ ET
BT 311.179 538.576 Td /F4 9.8 Tf  [(ventricular tachycardia \(CPVT\) )] TJ ET
0.267 0.267 0.267 rg
BT 455.850 538.576 Td /F4 8.7 Tf  [(5)] TJ ET
BT 311.179 527.730 Td /F4 8.7 Tf  [(17)] TJ ET
BT 320.817 527.730 Td /F4 8.7 Tf  [(30)] TJ ET
BT 330.454 527.730 Td /F4 8.7 Tf  [(31)] TJ ET
0.965 0.965 0.965 rg
471.281 523.915 109.219 36.089 re f
0.267 0.267 0.267 rg
471.281 559.630 109.594 0.750 re f
580.125 523.540 0.750 36.839 re f
0.271 0.267 0.267 rg
BT 475.781 550.481 Td /F4 9.8 Tf  [(Brugada syndrome )] TJ ET
BT 475.781 538.576 Td /F4 9.8 Tf  [(\(BrS\) )] TJ ET
0.267 0.267 0.267 rg
BT 502.320 538.576 Td /F4 8.7 Tf  [(17)] TJ ET
BT 511.958 538.576 Td /F4 8.7 Tf  [(32)] TJ ET
BT 521.595 538.576 Td /F4 8.7 Tf  [(33)] TJ ET
BT 531.232 538.576 Td /F4 8.7 Tf  [(34)] TJ ET
BT 540.870 538.576 Td /F4 8.7 Tf  [(35)] TJ ET
26.625 523.540 91.330 0.750 re f
26.625 484.765 0.750 39.525 re f
0.271 0.267 0.267 rg
BT 31.875 513.685 Td /F1 9.8 Tf  [(Prevalence)] TJ ET
0.267 0.267 0.267 rg
117.205 523.540 93.601 0.750 re f
117.205 484.765 0.750 39.525 re f
0.271 0.267 0.267 rg
BT 122.455 513.685 Td /F1 9.8 Tf  [(1:5,000 to 1:2,000)] TJ ET
0.267 0.267 0.267 rg
210.056 523.540 96.998 0.750 re f
210.056 484.765 0.750 39.525 re f
0.271 0.267 0.267 rg
BT 215.306 513.685 Td /F1 9.8 Tf  [(Rare � fewer than )] TJ ET
BT 215.306 506.054 Td /F1 9.8 Tf  [(30 cases published)] TJ ET
0.267 0.267 0.267 rg
306.304 523.540 165.351 0.750 re f
306.304 484.765 0.750 39.525 re f
0.271 0.267 0.267 rg
BT 311.554 513.685 Td /F1 9.8 Tf  [(1:7,000 to 1:10,000)] TJ ET
0.267 0.267 0.267 rg
470.906 523.540 109.969 0.750 re f
470.906 484.765 0.750 39.525 re f
580.125 484.765 0.750 39.525 re f
0.271 0.267 0.267 rg
BT 476.156 513.685 Td /F1 9.8 Tf  [(1:800 \(Japan\); )] TJ ET
BT 476.156 506.054 Td /F1 9.8 Tf  [(1:6,000 \(U.S. & )] TJ ET
BT 476.156 498.423 Td /F1 9.8 Tf  [(Europe\) type 1 ECG )] TJ ET
BT 476.156 490.792 Td /F1 9.8 Tf  [(pattern)] TJ ET
0.267 0.267 0.267 rg
26.625 484.765 91.330 0.750 re f
26.625 453.622 0.750 31.894 re f
0.271 0.267 0.267 rg
BT 31.875 474.910 Td /F1 9.8 Tf  [(Annual mortality )] TJ ET
BT 31.875 467.279 Td /F1 9.8 Tf  [(rate)] TJ ET
0.267 0.267 0.267 rg
117.205 484.765 93.601 0.750 re f
117.205 453.622 0.750 31.894 re f
0.271 0.267 0.267 rg
BT 122.455 474.910 Td /F1 9.8 Tf  [(0.3% \(LQT1\))] TJ ET
BT 122.455 467.279 Td /F1 9.8 Tf  [(0.6% \(LQT2\))] TJ ET
BT 122.455 459.648 Td /F1 9.8 Tf  [(0.56% \(LQT3\))] TJ ET
0.267 0.267 0.267 rg
210.056 484.765 96.998 0.750 re f
210.056 453.622 0.750 31.894 re f
0.271 0.267 0.267 rg
BT 215.306 474.910 Td /F1 9.8 Tf  [(Unidentified)] TJ ET
0.267 0.267 0.267 rg
306.304 484.765 165.351 0.750 re f
306.304 453.622 0.750 31.894 re f
0.271 0.267 0.267 rg
BT 311.554 474.910 Td /F1 9.8 Tf  [(3.1%)] TJ ET
0.267 0.267 0.267 rg
470.906 484.765 109.969 0.750 re f
470.906 453.622 0.750 31.894 re f
580.125 453.622 0.750 31.894 re f
0.271 0.267 0.267 rg
BT 476.156 474.910 Td /F1 9.8 Tf  [(4% \(pts. with type 1 )] TJ ET
BT 476.156 467.279 Td /F1 9.8 Tf  [(ECG pattern\))] TJ ET
0.267 0.267 0.267 rg
26.625 453.622 91.330 0.750 re f
26.625 430.109 0.750 24.263 re f
0.271 0.267 0.267 rg
BT 31.875 443.767 Td /F1 9.8 Tf  [(Mean age of first )] TJ ET
BT 31.875 436.135 Td /F1 9.8 Tf  [(event)] TJ ET
0.267 0.267 0.267 rg
117.205 453.622 93.601 0.750 re f
117.205 430.109 0.750 24.263 re f
0.271 0.267 0.267 rg
BT 122.455 443.767 Td /F1 9.8 Tf  [(14 � 12 yrs.)] TJ ET
0.267 0.267 0.267 rg
210.056 453.622 96.998 0.750 re f
210.056 430.109 0.750 24.263 re f
0.271 0.267 0.267 rg
BT 215.306 443.767 Td /F1 9.8 Tf  [(40 � 24 yrs.)] TJ ET
0.267 0.267 0.267 rg
306.304 453.622 165.351 0.750 re f
306.304 430.109 0.750 24.263 re f
0.271 0.267 0.267 rg
BT 311.554 443.767 Td /F1 9.8 Tf  [(15 � 10 yrs.)] TJ ET
0.267 0.267 0.267 rg
470.906 453.622 109.969 0.750 re f
470.906 430.109 0.750 24.263 re f
580.125 430.109 0.750 24.263 re f
0.271 0.267 0.267 rg
BT 476.156 443.767 Td /F1 9.8 Tf  [(42 � 16 yrs. \(pts. with )] TJ ET
BT 476.156 436.135 Td /F1 9.8 Tf  [(type 1 ECG\))] TJ ET
0.267 0.267 0.267 rg
26.625 430.109 91.330 0.750 re f
26.625 406.597 91.330 0.750 re f
26.625 406.597 0.750 24.263 re f
0.271 0.267 0.267 rg
BT 31.875 420.254 Td /F1 9.8 Tf  [(Diagnostic Yield � )] TJ ET
BT 31.875 412.623 Td /F1 9.8 Tf  [(Genetic Testing)] TJ ET
0.267 0.267 0.267 rg
117.205 430.109 93.601 0.750 re f
117.205 406.597 93.601 0.750 re f
117.205 406.597 0.750 24.263 re f
0.271 0.267 0.267 rg
BT 122.455 420.254 Td /F1 9.8 Tf  [(75-80%)] TJ ET
0.267 0.267 0.267 rg
210.056 430.109 96.998 0.750 re f
210.056 406.597 96.998 0.750 re f
210.056 406.597 0.750 24.263 re f
0.271 0.267 0.267 rg
BT 215.306 420.254 Td /F1 9.8 Tf  [(15-20%)] TJ ET
0.267 0.267 0.267 rg
306.304 430.109 165.351 0.750 re f
306.304 406.597 165.351 0.750 re f
306.304 406.597 0.750 24.263 re f
0.271 0.267 0.267 rg
BT 311.554 420.254 Td /F1 9.8 Tf  [(65-75%)] TJ ET
0.267 0.267 0.267 rg
470.906 430.109 109.969 0.750 re f
470.906 406.597 109.969 0.750 re f
470.906 406.597 0.750 24.263 re f
580.125 406.597 0.750 24.263 re f
0.271 0.267 0.267 rg
BT 476.156 420.254 Td /F1 9.8 Tf  [(11-40% \(see Clinical )] TJ ET
BT 476.156 412.623 Td /F1 9.8 Tf  [(Validity\))] TJ ET
BT 26.250 351.698 Td /F1 9.8 Tf  [(In the case of LQTS, the specific genotype has prognostic value)] TJ ET
0.267 0.267 0.267 rg
BT 302.107 353.205 Td /F4 8.7 Tf  [(1)] TJ ET
BT 306.925 353.205 Td /F4 8.7 Tf  [(6)] TJ ET
0.271 0.267 0.267 rg
BT 311.744 351.698 Td /F1 9.8 Tf  [(. In studies ranging from 250 to 300,000 genotyped )] TJ ET
BT 26.250 339.793 Td /F1 9.8 Tf  [(individuals through age 60 drawn from the International LQTS Registry, the LQT3 genotype has demonstrated a 5- to 8-fold )] TJ ET
BT 26.250 327.888 Td /F1 9.8 Tf  [(higher risk for life-threatening events compared to the LQT1 and 2 genotypes)] TJ ET
0.267 0.267 0.267 rg
BT 358.998 329.396 Td /F4 8.7 Tf  [(36)] TJ ET
0.271 0.267 0.267 rg
BT 368.635 327.888 Td /F1 9.8 Tf  [(. The LQT2 genotype displays a risk )] TJ ET
BT 26.250 315.984 Td /F1 9.8 Tf  [(intermediate between LQT1 and LQT3)] TJ ET
0.267 0.267 0.267 rg
BT 192.624 317.491 Td /F4 8.7 Tf  [(36)] TJ ET
0.271 0.267 0.267 rg
BT 202.261 315.984 Td /F1 9.8 Tf  [(, though the statistical strength and ordering of this relationship depends on age, sex, )] TJ ET
BT 26.250 304.079 Td /F1 9.8 Tf  [(and source of the cohort)] TJ ET
0.267 0.267 0.267 rg
BT 131.394 305.586 Td /F4 8.7 Tf  [(10)] TJ ET
BT 141.031 305.586 Td /F4 8.7 Tf  [(37)] TJ ET
0.271 0.267 0.267 rg
BT 150.669 304.079 Td /F1 9.8 Tf  [(. Subgroup analyses have more precisely defined the impact of QTc duration and genotype in )] TJ ET
BT 26.250 292.174 Td /F1 9.8 Tf  [(children and adolescents with LQT1 and 2)] TJ ET
0.267 0.267 0.267 rg
BT 208.341 293.681 Td /F4 8.7 Tf  [(38)] TJ ET
0.271 0.267 0.267 rg
BT 217.978 292.174 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 255.572 Td /F4 12.0 Tf  [(Published Reviews, Recommendations and Guidelines)] TJ ET
BT 26.250 235.617 Td /F5 9.8 Tf  [(Systematic evidence reviews)] TJ ET
BT 26.250 216.213 Td /F1 9.8 Tf  [(The Hayes Inc. Genetic Test Evaluation \(GTE\) Program has prepared three evaluations of ion channelopathies: long QT )] TJ ET
BT 26.250 204.308 Td /F1 9.8 Tf  [(syndrome, CPVT, and Brugada syndrome. These reviews were based on studies of primary literature retrieved from PUBMED )] TJ ET
BT 26.250 192.403 Td /F1 9.8 Tf  [(and Embase in the following date ranges: LQTS � January 1, 1996 to June 16, 2009; CPVT � January 1, 1996 to February 10, )] TJ ET
BT 26.250 180.498 Td /F1 9.8 Tf  [(2010; and Brugada syndrome � January 1, 1996 to August 3, 2010)] TJ ET
0.267 0.267 0.267 rg
BT 314.596 182.006 Td /F4 8.7 Tf  [(39)] TJ ET
0.271 0.267 0.267 rg
BT 324.234 180.498 Td /F1 9.8 Tf  [(. DNA Direct, Inc. has published two systematic reviews of )] TJ ET
BT 26.250 168.594 Td /F1 9.8 Tf  [(LQTS genetic testing through its Genomic Medicine Institute. The reviews, which the company makes available with interactive )] TJ ET
BT 26.250 156.689 Td /F1 9.8 Tf  [(tools and decision support, are based on studies of primary patient data published between 2001 and 2008)] TJ ET
0.267 0.267 0.267 rg
BT 486.928 158.196 Td /F4 8.7 Tf  [(40)] TJ ET
0.271 0.267 0.267 rg
BT 496.565 156.689 Td /F1 9.8 Tf  [(. BlueCross )] TJ ET
BT 26.250 144.784 Td /F1 9.8 Tf  [(BlueShield Association and Kaiser Permanente published a systematic review of genetic testing for long QT syndrome through )] TJ ET
BT 26.250 132.879 Td /F1 9.8 Tf  [(the BlueCross BlueShield Technology Evaluation Center \(BCBS Tec\))] TJ ET
0.267 0.267 0.267 rg
BT 324.824 134.387 Td /F4 8.7 Tf  [(41)] TJ ET
0.271 0.267 0.267 rg
BT 334.462 132.879 Td /F1 9.8 Tf  [(. The review was based on studies of primary patient )] TJ ET
BT 26.250 120.975 Td /F1 9.8 Tf  [(data appearing in Medline and PUBMED published between 1990 and October 2007. The Australia and New Zealand Horizon )] TJ ET
BT 26.250 109.070 Td /F1 9.8 Tf  [(Scanning Network released a Horizon Scanning Report on genetic testing for congenital long QT syndrome based principally on )] TJ ET
BT 26.250 97.165 Td /F1 9.8 Tf  [(nine peer-reviewed articles, and detailing safety \(e.g., false negatives\), effectiveness, clinical utility \(cost-effectiveness\), and )] TJ ET
BT 26.250 85.260 Td /F1 9.8 Tf  [(ethical \(consent and privacy, harms from testing, access\) considerations)] TJ ET
0.267 0.267 0.267 rg
BT 337.821 86.768 Td /F4 8.7 Tf  [(42)] TJ ET
0.271 0.267 0.267 rg
BT 347.458 85.260 Td /F1 9.8 Tf  [(. Investigative teams have published comprehensive )] TJ ET
BT 26.250 73.356 Td /F1 9.8 Tf  [(clinical-epidemiologic reviews of both long QT syndrome as a family and several of the other channelopathies under Human )] TJ ET
BT 26.250 61.451 Td /F1 9.8 Tf  [(Genome Epidemiology \(HuGE\) reviews \(e.g., long QT syndrome)] TJ ET
0.267 0.267 0.267 rg
BT 304.213 62.958 Td /F4 8.7 Tf  [(21)] TJ ET
0.271 0.267 0.267 rg
BT 313.850 61.451 Td /F1 9.8 Tf  [(\) and GeneReviews \(e.g., Brugada syndrome)] TJ ET
0.267 0.267 0.267 rg
BT 509.474 62.958 Td /F4 8.7 Tf  [(43)] TJ ET
0.271 0.267 0.267 rg
BT 519.111 61.451 Td /F1 9.8 Tf  [(\).)] TJ ET
Q
q
15.000 32.165 577.500 744.835 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F1 9.8 Tf  [(accommodated by some labs)] TJ ET
0.267 0.267 0.267 rg
BT 153.049 768.983 Td /F4 8.7 Tf  [(17)] TJ ET
BT 162.686 768.983 Td /F4 8.7 Tf  [(18)] TJ ET
0.271 0.267 0.267 rg
BT 172.323 767.476 Td /F1 9.8 Tf  [(. Detailed results are provided for each test panel, typically with a description of known )] TJ ET
BT 26.250 755.571 Td /F1 9.8 Tf  [(literature on any identified mutation and its likelihood to cause disease. Focused testing for a single mutation relevant to a )] TJ ET
BT 26.250 743.667 Td /F1 9.8 Tf  [(patient�s family, rather than a panel of potentially involved genes, is available at a lower cost.)] TJ ET
BT 26.250 707.064 Td /F4 12.0 Tf  [(Public Health Importance)] TJ ET
BT 26.250 687.110 Td /F1 9.8 Tf  [(The public health importance of these inherited arrhythmia syndromes is highlighted by their potential lethality, mostly due to )] TJ ET
BT 26.250 675.205 Td /F1 9.8 Tf  [(ventricular tachyarrhythmias)] TJ ET
0.267 0.267 0.267 rg
BT 148.154 676.712 Td /F4 8.7 Tf  [(20)] TJ ET
0.271 0.267 0.267 rg
BT 157.792 675.205 Td /F1 9.8 Tf  [(. Long QT syndrome may be responsible for as many as 3,000 unexpected deaths in children )] TJ ET
BT 26.250 663.300 Td /F1 9.8 Tf  [(and young adults annually in the United States)] TJ ET
0.267 0.267 0.267 rg
BT 227.324 664.808 Td /F4 8.7 Tf  [(21)] TJ ET
0.271 0.267 0.267 rg
BT 236.962 663.300 Td /F1 9.8 Tf  [(. Catecholaminergic polymorphic ventricular tachycardia carries a high )] TJ ET
BT 26.250 651.396 Td /F1 9.8 Tf  [(mortality in untreated cases)] TJ ET
0.267 0.267 0.267 rg
BT 145.463 652.903 Td /F4 8.7 Tf  [(5)] TJ ET
BT 150.282 652.903 Td /F4 8.7 Tf  [(7)] TJ ET
0.271 0.267 0.267 rg
BT 155.101 651.396 Td /F1 9.8 Tf  [(. The current state of technology, however, does not enable arrhythmia screening of broad, )] TJ ET
BT 26.250 639.491 Td /F1 9.8 Tf  [(potentially at-risk populations � athletes, all children, all patients exposed to QT-prolonging drugs, or all patients with a history of )] TJ ET
BT 26.250 627.586 Td /F1 9.8 Tf  [(syncope)] TJ ET
0.267 0.267 0.267 rg
BT 62.559 629.093 Td /F4 8.7 Tf  [(6)] TJ ET
BT 67.378 629.093 Td /F4 8.7 Tf  [(16)] TJ ET
0.271 0.267 0.267 rg
BT 77.015 627.586 Td /F1 9.8 Tf  [(. Subpopulations of sudden death victims are of great interest. It is estimated that approximately 25-35% of autopsy-)] TJ ET
BT 26.250 615.681 Td /F1 9.8 Tf  [(negative or unexplained sudden cardiac death in the young, and 10% of sudden infant death \(SIDS\) may be attributable to )] TJ ET
BT 26.250 603.777 Td /F1 9.8 Tf  [(mutations in either LQTS or CPVT susceptibility genes)] TJ ET
0.267 0.267 0.267 rg
BT 261.420 605.284 Td /F4 8.7 Tf  [(22)] TJ ET
0.271 0.267 0.267 rg
BT 271.057 603.777 Td /F1 9.8 Tf  [(. Brugada syndrome may be responsible for 4-15% of unexpected )] TJ ET
BT 26.250 591.872 Td /F1 9.8 Tf  [(sudden deaths, particularly in individuals with an apparently normal heart)] TJ ET
0.267 0.267 0.267 rg
BT 340.551 593.379 Td /F4 8.7 Tf  [(23)] TJ ET
BT 350.188 593.379 Td /F4 8.7 Tf  [(24)] TJ ET
BT 359.826 593.379 Td /F4 8.7 Tf  [(25)] TJ ET
0.271 0.267 0.267 rg
BT 369.463 591.872 Td /F1 9.8 Tf  [(.)] TJ ET
q
26.250 568.255 555.000 13.736 re W n
0.271 0.267 0.267 rg
BT 26.250 571.002 Td /F1 9.8 Tf  [(Table of Cardiac Ion Channelopathies)] TJ ET
Q
1.000 1.000 1.000 rg
26.250 406.222 555.000 154.533 re f
0.965 0.965 0.965 rg
27.000 523.915 90.580 36.089 re f
0.267 0.267 0.267 rg
26.625 559.630 90.955 0.750 re f
26.625 523.540 0.750 36.839 re f
0.965 0.965 0.965 rg
117.580 523.915 92.851 36.089 re f
0.267 0.267 0.267 rg
117.580 559.630 92.851 0.750 re f
0.271 0.267 0.267 rg
BT 122.080 550.481 Td /F4 9.8 Tf  [(Long QT )] TJ ET
BT 122.080 538.576 Td /F4 9.8 Tf  [(syndrome )] TJ ET
BT 122.080 526.671 Td /F4 9.8 Tf  [(\(LQTS\) )] TJ ET
0.267 0.267 0.267 rg
BT 157.288 526.671 Td /F4 8.7 Tf  [(17)] TJ ET
BT 166.925 526.671 Td /F4 8.7 Tf  [(26)] TJ ET
BT 176.562 526.671 Td /F4 8.7 Tf  [(27)] TJ ET
BT 186.200 526.671 Td /F4 8.7 Tf  [(28)] TJ ET
BT 195.837 526.671 Td /F4 8.7 Tf  [(75)] TJ ET
0.965 0.965 0.965 rg
210.431 523.915 96.248 36.089 re f
0.267 0.267 0.267 rg
210.431 559.630 96.248 0.750 re f
0.271 0.267 0.267 rg
BT 214.931 550.481 Td /F4 9.8 Tf  [(Short QT )] TJ ET
BT 214.931 538.576 Td /F4 9.8 Tf  [(syndrome \(SQTS\) )] TJ ET
0.267 0.267 0.267 rg
BT 214.931 527.730 Td /F4 8.7 Tf  [(17)] TJ ET
BT 224.569 527.730 Td /F4 8.7 Tf  [(18)] TJ ET
BT 234.206 527.730 Td /F4 8.7 Tf  [(29)] TJ ET
0.965 0.965 0.965 rg
306.679 523.915 164.601 36.089 re f
0.267 0.267 0.267 rg
306.679 559.630 164.601 0.750 re f
0.271 0.267 0.267 rg
BT 311.179 550.481 Td /F4 9.8 Tf  [(Catecholaminergic polymorphic )] TJ ET
BT 311.179 538.576 Td /F4 9.8 Tf  [(ventricular tachycardia \(CPVT\) )] TJ ET
0.267 0.267 0.267 rg
BT 455.850 538.576 Td /F4 8.7 Tf  [(5)] TJ ET
BT 311.179 527.730 Td /F4 8.7 Tf  [(17)] TJ ET
BT 320.817 527.730 Td /F4 8.7 Tf  [(30)] TJ ET
BT 330.454 527.730 Td /F4 8.7 Tf  [(31)] TJ ET
0.965 0.965 0.965 rg
471.281 523.915 109.219 36.089 re f
0.267 0.267 0.267 rg
471.281 559.630 109.594 0.750 re f
580.125 523.540 0.750 36.839 re f
0.271 0.267 0.267 rg
BT 475.781 550.481 Td /F4 9.8 Tf  [(Brugada syndrome )] TJ ET
BT 475.781 538.576 Td /F4 9.8 Tf  [(\(BrS\) )] TJ ET
0.267 0.267 0.267 rg
BT 502.320 538.576 Td /F4 8.7 Tf  [(17)] TJ ET
BT 511.958 538.576 Td /F4 8.7 Tf  [(32)] TJ ET
BT 521.595 538.576 Td /F4 8.7 Tf  [(33)] TJ ET
BT 531.232 538.576 Td /F4 8.7 Tf  [(34)] TJ ET
BT 540.870 538.576 Td /F4 8.7 Tf  [(35)] TJ ET
26.625 523.540 91.330 0.750 re f
26.625 484.765 0.750 39.525 re f
0.271 0.267 0.267 rg
BT 31.875 513.685 Td /F1 9.8 Tf  [(Prevalence)] TJ ET
0.267 0.267 0.267 rg
117.205 523.540 93.601 0.750 re f
117.205 484.765 0.750 39.525 re f
0.271 0.267 0.267 rg
BT 122.455 513.685 Td /F1 9.8 Tf  [(1:5,000 to 1:2,000)] TJ ET
0.267 0.267 0.267 rg
210.056 523.540 96.998 0.750 re f
210.056 484.765 0.750 39.525 re f
0.271 0.267 0.267 rg
BT 215.306 513.685 Td /F1 9.8 Tf  [(Rare � fewer than )] TJ ET
BT 215.306 506.054 Td /F1 9.8 Tf  [(30 cases published)] TJ ET
0.267 0.267 0.267 rg
306.304 523.540 165.351 0.750 re f
306.304 484.765 0.750 39.525 re f
0.271 0.267 0.267 rg
BT 311.554 513.685 Td /F1 9.8 Tf  [(1:7,000 to 1:10,000)] TJ ET
0.267 0.267 0.267 rg
470.906 523.540 109.969 0.750 re f
470.906 484.765 0.750 39.525 re f
580.125 484.765 0.750 39.525 re f
0.271 0.267 0.267 rg
BT 476.156 513.685 Td /F1 9.8 Tf  [(1:800 \(Japan\); )] TJ ET
BT 476.156 506.054 Td /F1 9.8 Tf  [(1:6,000 \(U.S. & )] TJ ET
BT 476.156 498.423 Td /F1 9.8 Tf  [(Europe\) type 1 ECG )] TJ ET
BT 476.156 490.792 Td /F1 9.8 Tf  [(pattern)] TJ ET
0.267 0.267 0.267 rg
26.625 484.765 91.330 0.750 re f
26.625 453.622 0.750 31.894 re f
0.271 0.267 0.267 rg
BT 31.875 474.910 Td /F1 9.8 Tf  [(Annual mortality )] TJ ET
BT 31.875 467.279 Td /F1 9.8 Tf  [(rate)] TJ ET
0.267 0.267 0.267 rg
117.205 484.765 93.601 0.750 re f
117.205 453.622 0.750 31.894 re f
0.271 0.267 0.267 rg
BT 122.455 474.910 Td /F1 9.8 Tf  [(0.3% \(LQT1\))] TJ ET
BT 122.455 467.279 Td /F1 9.8 Tf  [(0.6% \(LQT2\))] TJ ET
BT 122.455 459.648 Td /F1 9.8 Tf  [(0.56% \(LQT3\))] TJ ET
0.267 0.267 0.267 rg
210.056 484.765 96.998 0.750 re f
210.056 453.622 0.750 31.894 re f
0.271 0.267 0.267 rg
BT 215.306 474.910 Td /F1 9.8 Tf  [(Unidentified)] TJ ET
0.267 0.267 0.267 rg
306.304 484.765 165.351 0.750 re f
306.304 453.622 0.750 31.894 re f
0.271 0.267 0.267 rg
BT 311.554 474.910 Td /F1 9.8 Tf  [(3.1%)] TJ ET
0.267 0.267 0.267 rg
470.906 484.765 109.969 0.750 re f
470.906 453.622 0.750 31.894 re f
580.125 453.622 0.750 31.894 re f
0.271 0.267 0.267 rg
BT 476.156 474.910 Td /F1 9.8 Tf  [(4% \(pts. with type 1 )] TJ ET
BT 476.156 467.279 Td /F1 9.8 Tf  [(ECG pattern\))] TJ ET
0.267 0.267 0.267 rg
26.625 453.622 91.330 0.750 re f
26.625 430.109 0.750 24.263 re f
0.271 0.267 0.267 rg
BT 31.875 443.767 Td /F1 9.8 Tf  [(Mean age of first )] TJ ET
BT 31.875 436.135 Td /F1 9.8 Tf  [(event)] TJ ET
0.267 0.267 0.267 rg
117.205 453.622 93.601 0.750 re f
117.205 430.109 0.750 24.263 re f
0.271 0.267 0.267 rg
BT 122.455 443.767 Td /F1 9.8 Tf  [(14 � 12 yrs.)] TJ ET
0.267 0.267 0.267 rg
210.056 453.622 96.998 0.750 re f
210.056 430.109 0.750 24.263 re f
0.271 0.267 0.267 rg
BT 215.306 443.767 Td /F1 9.8 Tf  [(40 � 24 yrs.)] TJ ET
0.267 0.267 0.267 rg
306.304 453.622 165.351 0.750 re f
306.304 430.109 0.750 24.263 re f
0.271 0.267 0.267 rg
BT 311.554 443.767 Td /F1 9.8 Tf  [(15 � 10 yrs.)] TJ ET
0.267 0.267 0.267 rg
470.906 453.622 109.969 0.750 re f
470.906 430.109 0.750 24.263 re f
580.125 430.109 0.750 24.263 re f
0.271 0.267 0.267 rg
BT 476.156 443.767 Td /F1 9.8 Tf  [(42 � 16 yrs. \(pts. with )] TJ ET
BT 476.156 436.135 Td /F1 9.8 Tf  [(type 1 ECG\))] TJ ET
0.267 0.267 0.267 rg
26.625 430.109 91.330 0.750 re f
26.625 406.597 91.330 0.750 re f
26.625 406.597 0.750 24.263 re f
0.271 0.267 0.267 rg
BT 31.875 420.254 Td /F1 9.8 Tf  [(Diagnostic Yield � )] TJ ET
BT 31.875 412.623 Td /F1 9.8 Tf  [(Genetic Testing)] TJ ET
0.267 0.267 0.267 rg
117.205 430.109 93.601 0.750 re f
117.205 406.597 93.601 0.750 re f
117.205 406.597 0.750 24.263 re f
0.271 0.267 0.267 rg
BT 122.455 420.254 Td /F1 9.8 Tf  [(75-80%)] TJ ET
0.267 0.267 0.267 rg
210.056 430.109 96.998 0.750 re f
210.056 406.597 96.998 0.750 re f
210.056 406.597 0.750 24.263 re f
0.271 0.267 0.267 rg
BT 215.306 420.254 Td /F1 9.8 Tf  [(15-20%)] TJ ET
0.267 0.267 0.267 rg
306.304 430.109 165.351 0.750 re f
306.304 406.597 165.351 0.750 re f
306.304 406.597 0.750 24.263 re f
0.271 0.267 0.267 rg
BT 311.554 420.254 Td /F1 9.8 Tf  [(65-75%)] TJ ET
0.267 0.267 0.267 rg
470.906 430.109 109.969 0.750 re f
470.906 406.597 109.969 0.750 re f
470.906 406.597 0.750 24.263 re f
580.125 406.597 0.750 24.263 re f
0.271 0.267 0.267 rg
BT 476.156 420.254 Td /F1 9.8 Tf  [(11-40% \(see Clinical )] TJ ET
BT 476.156 412.623 Td /F1 9.8 Tf  [(Validity\))] TJ ET
BT 26.250 351.698 Td /F1 9.8 Tf  [(In the case of LQTS, the specific genotype has prognostic value)] TJ ET
0.267 0.267 0.267 rg
BT 302.107 353.205 Td /F4 8.7 Tf  [(1)] TJ ET
BT 306.925 353.205 Td /F4 8.7 Tf  [(6)] TJ ET
0.271 0.267 0.267 rg
BT 311.744 351.698 Td /F1 9.8 Tf  [(. In studies ranging from 250 to 300,000 genotyped )] TJ ET
BT 26.250 339.793 Td /F1 9.8 Tf  [(individuals through age 60 drawn from the International LQTS Registry, the LQT3 genotype has demonstrated a 5- to 8-fold )] TJ ET
BT 26.250 327.888 Td /F1 9.8 Tf  [(higher risk for life-threatening events compared to the LQT1 and 2 genotypes)] TJ ET
0.267 0.267 0.267 rg
BT 358.998 329.396 Td /F4 8.7 Tf  [(36)] TJ ET
0.271 0.267 0.267 rg
BT 368.635 327.888 Td /F1 9.8 Tf  [(. The LQT2 genotype displays a risk )] TJ ET
BT 26.250 315.984 Td /F1 9.8 Tf  [(intermediate between LQT1 and LQT3)] TJ ET
0.267 0.267 0.267 rg
BT 192.624 317.491 Td /F4 8.7 Tf  [(36)] TJ ET
0.271 0.267 0.267 rg
BT 202.261 315.984 Td /F1 9.8 Tf  [(, though the statistical strength and ordering of this relationship depends on age, sex, )] TJ ET
BT 26.250 304.079 Td /F1 9.8 Tf  [(and source of the cohort)] TJ ET
0.267 0.267 0.267 rg
BT 131.394 305.586 Td /F4 8.7 Tf  [(10)] TJ ET
BT 141.031 305.586 Td /F4 8.7 Tf  [(37)] TJ ET
0.271 0.267 0.267 rg
BT 150.669 304.079 Td /F1 9.8 Tf  [(. Subgroup analyses have more precisely defined the impact of QTc duration and genotype in )] TJ ET
BT 26.250 292.174 Td /F1 9.8 Tf  [(children and adolescents with LQT1 and 2)] TJ ET
0.267 0.267 0.267 rg
BT 208.341 293.681 Td /F4 8.7 Tf  [(38)] TJ ET
0.271 0.267 0.267 rg
BT 217.978 292.174 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 255.572 Td /F4 12.0 Tf  [(Published Reviews, Recommendations and Guidelines)] TJ ET
BT 26.250 235.617 Td /F5 9.8 Tf  [(Systematic evidence reviews)] TJ ET
BT 26.250 216.213 Td /F1 9.8 Tf  [(The Hayes Inc. Genetic Test Evaluation \(GTE\) Program has prepared three evaluations of ion channelopathies: long QT )] TJ ET
BT 26.250 204.308 Td /F1 9.8 Tf  [(syndrome, CPVT, and Brugada syndrome. These reviews were based on studies of primary literature retrieved from PUBMED )] TJ ET
BT 26.250 192.403 Td /F1 9.8 Tf  [(and Embase in the following date ranges: LQTS � January 1, 1996 to June 16, 2009; CPVT � January 1, 1996 to February 10, )] TJ ET
BT 26.250 180.498 Td /F1 9.8 Tf  [(2010; and Brugada syndrome � January 1, 1996 to August 3, 2010)] TJ ET
0.267 0.267 0.267 rg
BT 314.596 182.006 Td /F4 8.7 Tf  [(39)] TJ ET
0.271 0.267 0.267 rg
BT 324.234 180.498 Td /F1 9.8 Tf  [(. DNA Direct, Inc. has published two systematic reviews of )] TJ ET
BT 26.250 168.594 Td /F1 9.8 Tf  [(LQTS genetic testing through its Genomic Medicine Institute. The reviews, which the company makes available with interactive )] TJ ET
BT 26.250 156.689 Td /F1 9.8 Tf  [(tools and decision support, are based on studies of primary patient data published between 2001 and 2008)] TJ ET
0.267 0.267 0.267 rg
BT 486.928 158.196 Td /F4 8.7 Tf  [(40)] TJ ET
0.271 0.267 0.267 rg
BT 496.565 156.689 Td /F1 9.8 Tf  [(. BlueCross )] TJ ET
BT 26.250 144.784 Td /F1 9.8 Tf  [(BlueShield Association and Kaiser Permanente published a systematic review of genetic testing for long QT syndrome through )] TJ ET
BT 26.250 132.879 Td /F1 9.8 Tf  [(the BlueCross BlueShield Technology Evaluation Center \(BCBS Tec\))] TJ ET
0.267 0.267 0.267 rg
BT 324.824 134.387 Td /F4 8.7 Tf  [(41)] TJ ET
0.271 0.267 0.267 rg
BT 334.462 132.879 Td /F1 9.8 Tf  [(. The review was based on studies of primary patient )] TJ ET
BT 26.250 120.975 Td /F1 9.8 Tf  [(data appearing in Medline and PUBMED published between 1990 and October 2007. The Australia and New Zealand Horizon )] TJ ET
BT 26.250 109.070 Td /F1 9.8 Tf  [(Scanning Network released a Horizon Scanning Report on genetic testing for congenital long QT syndrome based principally on )] TJ ET
BT 26.250 97.165 Td /F1 9.8 Tf  [(nine peer-reviewed articles, and detailing safety \(e.g., false negatives\), effectiveness, clinical utility \(cost-effectiveness\), and )] TJ ET
BT 26.250 85.260 Td /F1 9.8 Tf  [(ethical \(consent and privacy, harms from testing, access\) considerations)] TJ ET
0.267 0.267 0.267 rg
BT 337.821 86.768 Td /F4 8.7 Tf  [(42)] TJ ET
0.271 0.267 0.267 rg
BT 347.458 85.260 Td /F1 9.8 Tf  [(. Investigative teams have published comprehensive )] TJ ET
BT 26.250 73.356 Td /F1 9.8 Tf  [(clinical-epidemiologic reviews of both long QT syndrome as a family and several of the other channelopathies under Human )] TJ ET
BT 26.250 61.451 Td /F1 9.8 Tf  [(Genome Epidemiology \(HuGE\) reviews \(e.g., long QT syndrome)] TJ ET
0.267 0.267 0.267 rg
BT 304.213 62.958 Td /F4 8.7 Tf  [(21)] TJ ET
0.271 0.267 0.267 rg
BT 313.850 61.451 Td /F1 9.8 Tf  [(\) and GeneReviews \(e.g., Brugada syndrome)] TJ ET
0.267 0.267 0.267 rg
BT 509.474 62.958 Td /F4 8.7 Tf  [(43)] TJ ET
0.271 0.267 0.267 rg
BT 519.111 61.451 Td /F1 9.8 Tf  [(\).)] TJ ET
Q
q
0.000 0.000 0.000 rg
BT 291.710 19.825 Td /F1 11.0 Tf  [(2)] TJ ET
BT 25.000 19.825 Td /F1 11.0 Tf  [(PLOS Currents Evidence on Genomic Tests)] TJ ET

Q
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15.000 32.587 577.500 744.413 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F5 9.8 Tf  [(Recommendations by independent groups)] TJ ET
BT 26.250 748.071 Td /F1 9.8 Tf  [(Two independent reviews have concluded that genetic testing has diagnostic value, including for the identification of )] TJ ET
BT 26.250 736.167 Td /F1 9.8 Tf  [(asymptomatic heterozygotes, for all four syndromes; definitive prognostic value for LQTS and weak or contingent prognostic )] TJ ET
BT 26.250 724.262 Td /F1 9.8 Tf  [(value \(depending on the nature of the findings\) for CPVT and BrS; and practical value in the determination of therapy for LQTS )] TJ ET
BT 26.250 712.357 Td /F1 9.8 Tf  [(alone)] TJ ET
0.267 0.267 0.267 rg
BT 50.099 713.864 Td /F4 8.7 Tf  [(1)] TJ ET
BT 54.917 713.864 Td /F4 8.7 Tf  [(30)] TJ ET
0.271 0.267 0.267 rg
BT 64.555 712.357 Td /F1 9.8 Tf  [(. One of the teams also published an �evidence-based� genetic testing scoring system to compare the relative clinical )] TJ ET
BT 26.250 700.452 Td /F1 9.8 Tf  [(value of genetic testing over these conditions \(LQTS > CPVT > BrS > SQTS\))] TJ ET
0.267 0.267 0.267 rg
BT 357.633 701.960 Td /F4 8.7 Tf  [(44)] TJ ET
0.271 0.267 0.267 rg
BT 367.270 700.452 Td /F1 9.8 Tf  [(. SQTS�s low score is associated with paucity of )] TJ ET
BT 26.250 688.548 Td /F1 9.8 Tf  [(data, this condition having first been described in 2000)] TJ ET
0.267 0.267 0.267 rg
BT 261.459 690.055 Td /F4 8.7 Tf  [(15)] TJ ET
0.271 0.267 0.267 rg
BT 271.096 688.548 Td /F1 9.8 Tf  [(. Criteria on when to screen for each channelopathy, based on )] TJ ET
BT 26.250 676.643 Td /F1 9.8 Tf  [(consensus documents and primary literature from 1995 onward, are laid out by Tzou and Gerstenfeld)] TJ ET
0.267 0.267 0.267 rg
BT 462.485 678.150 Td /F4 8.7 Tf  [(15)] TJ ET
0.271 0.267 0.267 rg
BT 472.122 676.643 Td /F1 9.8 Tf  [(. This review concluded )] TJ ET
BT 26.250 664.738 Td /F1 9.8 Tf  [(that genetic testing can lead to genotype-specific therapy in the case of LQTS, and decisions about ICD placement for )] TJ ET
BT 26.250 652.833 Td /F1 9.8 Tf  [(malignant arrhythmias associated with CPVT and SQTS)] TJ ET
0.267 0.267 0.267 rg
BT 268.459 654.341 Td /F4 8.7 Tf  [(15)] TJ ET
0.271 0.267 0.267 rg
BT 278.097 652.833 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 633.429 Td /F5 9.8 Tf  [(Guidelines by independent groups)] TJ ET
BT 26.250 614.024 Td /F1 9.8 Tf  [(A 2007 consensus report by the U.S. National Heart, Lung, and Blood Institute and the Office of Rare Diseases on gene )] TJ ET
BT 26.250 602.119 Td /F1 9.8 Tf  [(mutations affecting ion channel function concluded that genetic testing for LQTS must be combined with clinical evaluation, and )] TJ ET
BT 26.250 590.214 Td /F1 9.8 Tf  [(noted lack of clarity in the proportion of SQTS cases that might be explained by the corresponding KCNH2, KCNJ2, and KCNQ1 )] TJ ET
BT 26.250 578.310 Td /F1 9.8 Tf  [(genes)] TJ ET
0.267 0.267 0.267 rg
BT 52.809 579.817 Td /F4 8.7 Tf  [(45)] TJ ET
0.271 0.267 0.267 rg
BT 62.446 578.310 Td /F1 9.8 Tf  [(. A 2011 Heart Rhythm Society \(HRS\) / European Heart Rhythm Association \(EHRA\) consensus statement further )] TJ ET
BT 26.250 566.405 Td /F1 9.8 Tf  [(states that LQTS genetic testing is recommended for any asymptomatic patient with idiopathic \(not attributable to QT prolonging )] TJ ET
BT 26.250 554.500 Td /F1 9.8 Tf  [(disease states or conditions\) QTc values > .48 s. \(prepuberty\) or > .50 s. \(adult\), and may be considered for QTc values >= .46 )] TJ ET
BT 26.250 542.595 Td /F1 9.8 Tf  [(and .48, respectively)] TJ ET
0.267 0.267 0.267 rg
BT 115.667 544.103 Td /F4 8.7 Tf  [(6)] TJ ET
0.271 0.267 0.267 rg
BT 120.486 542.595 Td /F1 9.8 Tf  [(. \(QTc = �heart rate-corrected QT interval,� as per the Bazett formula)] TJ ET
0.267 0.267 0.267 rg
BT 415.531 544.103 Td /F4 8.7 Tf  [(4)] TJ ET
0.271 0.267 0.267 rg
BT 420.349 542.595 Td /F1 9.8 Tf  [(.\) The Heart Rhythm UK Familial )] TJ ET
BT 26.250 530.691 Td /F1 9.8 Tf  [(Sudden Death Syndromes Statement Development Group published in 2008 a position statement on genetic testing for sudden )] TJ ET
BT 26.250 518.786 Td /F1 9.8 Tf  [(cardiac death syndromes based on a comprehensive review of English language publications, grading of the evidence, and )] TJ ET
BT 26.250 506.881 Td /F1 9.8 Tf  [(secondary review of the evidence by an external committee)] TJ ET
0.267 0.267 0.267 rg
BT 282.568 508.388 Td /F4 8.7 Tf  [(3)] TJ ET
0.271 0.267 0.267 rg
BT 287.386 506.881 Td /F1 9.8 Tf  [(. The Group followed with a position statement on ICD placement )] TJ ET
BT 26.250 494.976 Td /F1 9.8 Tf  [(for these conditions based on risk of SCD)] TJ ET
0.267 0.267 0.267 rg
BT 205.621 496.484 Td /F4 8.7 Tf  [(46)] TJ ET
0.271 0.267 0.267 rg
BT 215.258 494.976 Td /F1 9.8 Tf  [(. The first position statement and the more recent HRS/EHRA report recommend )] TJ ET
BT 26.250 483.072 Td /F1 9.8 Tf  [(genetic testing for all patients with a firm diagnosis of congenital LQTS and those with clinical features of CPVT \(due to its )] TJ ET
BT 26.250 471.167 Td /F1 9.8 Tf  [(severity, despite an acknowledged lower clinical sensitivity\), but that expert clinical and family history assessment are needed )] TJ ET
BT 26.250 459.262 Td /F1 9.8 Tf  [(when genetic testing is undertaken for borderline LQTS cases and known or suspected cases of BrS. Practice guidelines from )] TJ ET
BT 26.250 447.357 Td /F1 9.8 Tf  [(the American College of Cardiology / American Heart Association / European Society of Cardiology)] TJ ET
0.267 0.267 0.267 rg
BT 453.251 448.865 Td /F4 8.7 Tf  [(47)] TJ ET
0.271 0.267 0.267 rg
BT 462.889 447.357 Td /F1 9.8 Tf  [( have noted an evolving )] TJ ET
BT 26.250 435.453 Td /F1 9.8 Tf  [(role for genetic testing of LQTS in risk stratification and clinical decision making. Both independent reviews and professional )] TJ ET
BT 26.250 423.548 Td /F1 9.8 Tf  [(society guidelines agree that genetic testing by itself is not recommended in making a diagnosis or prognosis for BrS, though it )] TJ ET
BT 26.250 411.643 Td /F1 9.8 Tf  [(may be used to support clinical diagnosis, and early detection of at-risk relatives)] TJ ET
0.267 0.267 0.267 rg
BT 370.893 413.150 Td /F4 8.7 Tf  [(6)] TJ ET
BT 375.712 413.150 Td /F4 8.7 Tf  [(25)] TJ ET
BT 385.349 413.150 Td /F4 8.7 Tf  [(48)] TJ ET
0.271 0.267 0.267 rg
BT 394.986 411.643 Td /F1 9.8 Tf  [(. Several HRS / EHRA consensus )] TJ ET
BT 26.250 399.738 Td /F1 9.8 Tf  [(statements clarify that genetic testing can be useful in patients clinically suspected of having BrS with a type 1 \(�coved� ST )] TJ ET
BT 26.250 387.834 Td /F1 9.8 Tf  [(segment elevation\) ECG pattern, but that it is not indicated in the setting of an isolated type 2 \(less specific, �saddleback� ST )] TJ ET
BT 26.250 375.929 Td /F1 9.8 Tf  [(elevation\) or 3 \(either shape but less pronounced elevation\) pattern)] TJ ET
0.267 0.267 0.267 rg
BT 316.186 377.436 Td /F4 8.7 Tf  [(6)] TJ ET
BT 321.004 377.436 Td /F4 8.7 Tf  [(20)] TJ ET
BT 330.642 377.436 Td /F4 8.7 Tf  [(25)] TJ ET
0.271 0.267 0.267 rg
BT 340.279 375.929 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 339.326 Td /F4 12.0 Tf  [(Evidence Overview)] TJ ET
BT 26.250 319.372 Td /F5 9.8 Tf  [(Analytic Validity:)] TJ ET
BT 26.250 299.967 Td /F1 9.8 Tf  [(Commercially available channelopathy genetic testing \(CGT\) for LQTS, SQTS, CPVT, and BrS involves direct sequencing of )] TJ ET
BT 26.250 288.063 Td /F1 9.8 Tf  [(protein-coding portions and flanking regions of targeted exons following PCR amplification. Sequencing is performed in both )] TJ ET
BT 26.250 276.158 Td /F1 9.8 Tf  [(forward and reverse directions. Sequences are analyzed for heterozygous and homozygous variants using public reference )] TJ ET
BT 26.250 264.253 Td /F1 9.8 Tf  [(sequences)] TJ ET
0.267 0.267 0.267 rg
BT 73.401 265.760 Td /F4 8.7 Tf  [(17)] TJ ET
BT 83.038 265.760 Td /F4 8.7 Tf  [(41)] TJ ET
0.271 0.267 0.267 rg
BT 92.676 264.253 Td /F1 9.8 Tf  [(. For the FAMILION� test, variants detected in the initial analysis are confirmed by repeating the sequencing )] TJ ET
BT 26.250 252.348 Td /F1 9.8 Tf  [(twice in the forward and three times in the backward direction. Transgenomic reports a CGT error rate of < 1% )] TJ ET
0.267 0.267 0.267 rg
BT 503.912 253.856 Td /F4 8.7 Tf  [(17)] TJ ET
0.271 0.267 0.267 rg
BT 513.550 252.348 Td /F1 9.8 Tf  [(. GeneDx )] TJ ET
BT 26.250 240.444 Td /F1 9.8 Tf  [(indicates a 98% �technical sensitivity� for assessment of each of the four conditions)] TJ ET
0.267 0.267 0.267 rg
BT 384.445 241.951 Td /F4 8.7 Tf  [(18)] TJ ET
0.271 0.267 0.267 rg
BT 394.083 240.444 Td /F1 9.8 Tf  [(. The John Welsh Cardiovascular )] TJ ET
BT 26.250 228.539 Td /F1 9.8 Tf  [(Laboratory at Baylor College of Medicine makes available genetic diagnostic testing using DNA sequencing analysis for KCNJ2 )] TJ ET
BT 26.250 216.634 Td /F1 9.8 Tf  [(\(LQT7\) and CAV3 \(LQT9\) mutations. This facility reports approximately 99% detection of the exons that are sequenced)] TJ ET
0.267 0.267 0.267 rg
BT 539.432 218.141 Td /F4 8.7 Tf  [(49)] TJ ET
0.271 0.267 0.267 rg
BT 549.069 216.634 Td /F1 9.8 Tf  [(. )] TJ ET
BT 26.250 204.729 Td /F1 9.8 Tf  [(Failure to detect variants in the laboratory setting is attributed to refractoriness of the amplicon to analysis by direct DNA )] TJ ET
BT 26.250 192.825 Td /F1 9.8 Tf  [(sequencing or real-time PCR detection, sample mishandling, sample tracking errors, errors in data analysis, and other gene )] TJ ET
BT 26.250 180.920 Td /F1 9.8 Tf  [(specific issues \(see Clinical Validity\))] TJ ET
0.267 0.267 0.267 rg
BT 182.279 182.427 Td /F4 8.7 Tf  [(17)] TJ ET
0.271 0.267 0.267 rg
BT 191.917 180.920 Td /F1 9.8 Tf  [(. The FAMILION� analytic specificity approaches 100% for �Class I� \(deleterious or )] TJ ET
BT 26.250 169.015 Td /F1 9.8 Tf  [(probably deleterious\) mutations, and approximates 95% for �Class II� mutations \(of uncertain clinical significance � possibly )] TJ ET
BT 26.250 157.110 Td /F1 9.8 Tf  [(deleterious\))] TJ ET
0.267 0.267 0.267 rg
BT 77.184 158.618 Td /F4 8.7 Tf  [(41)] TJ ET
0.271 0.267 0.267 rg
BT 86.821 157.110 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 137.706 Td /F5 9.8 Tf  [(Clinical Validity:)] TJ ET
BT 26.250 118.301 Td /F1 9.8 Tf  [(The near perfect analytic sensitivities of these assays must be contrasted with the ability to detect genetic variants in the clinical )] TJ ET
BT 26.250 106.396 Td /F1 9.8 Tf  [(setting. The yield for the first 2,500 consecutive unrelated cases referred by physicians for commercially available long QT )] TJ ET
BT 26.250 94.491 Td /F1 9.8 Tf  [(syndrome genetic testing \(low-, intermediate-, and high-pretest probability\) was 36%; values in the literature range between 33 )] TJ ET
BT 26.250 82.587 Td /F1 9.8 Tf  [(and 39%)] TJ ET
0.267 0.267 0.267 rg
BT 64.733 84.094 Td /F4 8.7 Tf  [(50)] TJ ET
0.271 0.267 0.267 rg
BT 74.371 82.587 Td /F1 9.8 Tf  [(. Tester et al. reported greater yields of 72 to 78% using the 5 major LQTS genes for patients with the highest clinical )] TJ ET
BT 26.250 70.682 Td /F1 9.8 Tf  [(probability for LQTS \(Schwartz-Moss score >= 4 )] TJ ET
0.267 0.267 0.267 rg
BT 237.025 72.189 Td /F4 8.7 Tf  [(4)] TJ ET
0.271 0.267 0.267 rg
BT 241.844 70.682 Td /F1 9.8 Tf  [(\))] TJ ET
0.267 0.267 0.267 rg
BT 245.091 72.189 Td /F4 8.7 Tf  [(37)] TJ ET
0.271 0.267 0.267 rg
BT 254.728 70.682 Td /F1 9.8 Tf  [(. Transgenomic reports a 75 to 80% yield for such patients based upon )] TJ ET
BT 26.250 58.777 Td /F1 9.8 Tf  [(multiple data sets)] TJ ET
0.267 0.267 0.267 rg
BT 102.115 60.284 Td /F4 8.7 Tf  [(17)] TJ ET
BT 111.752 60.284 Td /F4 8.7 Tf  [(51)] TJ ET
0.271 0.267 0.267 rg
BT 121.389 58.777 Td /F1 9.8 Tf  [(. False negatives may be explained by a number of factors, including the existence of private mutations)] TJ ET
0.267 0.267 0.267 rg
BT 565.765 60.284 Td /F4 8.7 Tf  [(37)] TJ ET
0.271 0.267 0.267 rg
BT 575.403 58.777 Td /F1 9.8 Tf  [(, )] TJ ET
BT 26.250 46.872 Td /F1 9.8 Tf  [(the presence of non-targeted exons)] TJ ET
0.267 0.267 0.267 rg
BT 180.173 48.380 Td /F4 8.7 Tf  [(17)] TJ ET
0.271 0.267 0.267 rg
BT 189.811 46.872 Td /F1 9.8 Tf  [( and relevant introns outside tested splice sites)] TJ ET
0.267 0.267 0.267 rg
BT 391.948 48.380 Td /F4 8.7 Tf  [(16)] TJ ET
0.271 0.267 0.267 rg
BT 401.585 46.872 Td /F1 9.8 Tf  [(, and the existence of large deletion and )] TJ ET
Q
q
15.000 32.587 577.500 744.413 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F5 9.8 Tf  [(Recommendations by independent groups)] TJ ET
BT 26.250 748.071 Td /F1 9.8 Tf  [(Two independent reviews have concluded that genetic testing has diagnostic value, including for the identification of )] TJ ET
BT 26.250 736.167 Td /F1 9.8 Tf  [(asymptomatic heterozygotes, for all four syndromes; definitive prognostic value for LQTS and weak or contingent prognostic )] TJ ET
BT 26.250 724.262 Td /F1 9.8 Tf  [(value \(depending on the nature of the findings\) for CPVT and BrS; and practical value in the determination of therapy for LQTS )] TJ ET
BT 26.250 712.357 Td /F1 9.8 Tf  [(alone)] TJ ET
0.267 0.267 0.267 rg
BT 50.099 713.864 Td /F4 8.7 Tf  [(1)] TJ ET
BT 54.917 713.864 Td /F4 8.7 Tf  [(30)] TJ ET
0.271 0.267 0.267 rg
BT 64.555 712.357 Td /F1 9.8 Tf  [(. One of the teams also published an �evidence-based� genetic testing scoring system to compare the relative clinical )] TJ ET
BT 26.250 700.452 Td /F1 9.8 Tf  [(value of genetic testing over these conditions \(LQTS > CPVT > BrS > SQTS\))] TJ ET
0.267 0.267 0.267 rg
BT 357.633 701.960 Td /F4 8.7 Tf  [(44)] TJ ET
0.271 0.267 0.267 rg
BT 367.270 700.452 Td /F1 9.8 Tf  [(. SQTS�s low score is associated with paucity of )] TJ ET
BT 26.250 688.548 Td /F1 9.8 Tf  [(data, this condition having first been described in 2000)] TJ ET
0.267 0.267 0.267 rg
BT 261.459 690.055 Td /F4 8.7 Tf  [(15)] TJ ET
0.271 0.267 0.267 rg
BT 271.096 688.548 Td /F1 9.8 Tf  [(. Criteria on when to screen for each channelopathy, based on )] TJ ET
BT 26.250 676.643 Td /F1 9.8 Tf  [(consensus documents and primary literature from 1995 onward, are laid out by Tzou and Gerstenfeld)] TJ ET
0.267 0.267 0.267 rg
BT 462.485 678.150 Td /F4 8.7 Tf  [(15)] TJ ET
0.271 0.267 0.267 rg
BT 472.122 676.643 Td /F1 9.8 Tf  [(. This review concluded )] TJ ET
BT 26.250 664.738 Td /F1 9.8 Tf  [(that genetic testing can lead to genotype-specific therapy in the case of LQTS, and decisions about ICD placement for )] TJ ET
BT 26.250 652.833 Td /F1 9.8 Tf  [(malignant arrhythmias associated with CPVT and SQTS)] TJ ET
0.267 0.267 0.267 rg
BT 268.459 654.341 Td /F4 8.7 Tf  [(15)] TJ ET
0.271 0.267 0.267 rg
BT 278.097 652.833 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 633.429 Td /F5 9.8 Tf  [(Guidelines by independent groups)] TJ ET
BT 26.250 614.024 Td /F1 9.8 Tf  [(A 2007 consensus report by the U.S. National Heart, Lung, and Blood Institute and the Office of Rare Diseases on gene )] TJ ET
BT 26.250 602.119 Td /F1 9.8 Tf  [(mutations affecting ion channel function concluded that genetic testing for LQTS must be combined with clinical evaluation, and )] TJ ET
BT 26.250 590.214 Td /F1 9.8 Tf  [(noted lack of clarity in the proportion of SQTS cases that might be explained by the corresponding KCNH2, KCNJ2, and KCNQ1 )] TJ ET
BT 26.250 578.310 Td /F1 9.8 Tf  [(genes)] TJ ET
0.267 0.267 0.267 rg
BT 52.809 579.817 Td /F4 8.7 Tf  [(45)] TJ ET
0.271 0.267 0.267 rg
BT 62.446 578.310 Td /F1 9.8 Tf  [(. A 2011 Heart Rhythm Society \(HRS\) / European Heart Rhythm Association \(EHRA\) consensus statement further )] TJ ET
BT 26.250 566.405 Td /F1 9.8 Tf  [(states that LQTS genetic testing is recommended for any asymptomatic patient with idiopathic \(not attributable to QT prolonging )] TJ ET
BT 26.250 554.500 Td /F1 9.8 Tf  [(disease states or conditions\) QTc values > .48 s. \(prepuberty\) or > .50 s. \(adult\), and may be considered for QTc values >= .46 )] TJ ET
BT 26.250 542.595 Td /F1 9.8 Tf  [(and .48, respectively)] TJ ET
0.267 0.267 0.267 rg
BT 115.667 544.103 Td /F4 8.7 Tf  [(6)] TJ ET
0.271 0.267 0.267 rg
BT 120.486 542.595 Td /F1 9.8 Tf  [(. \(QTc = �heart rate-corrected QT interval,� as per the Bazett formula)] TJ ET
0.267 0.267 0.267 rg
BT 415.531 544.103 Td /F4 8.7 Tf  [(4)] TJ ET
0.271 0.267 0.267 rg
BT 420.349 542.595 Td /F1 9.8 Tf  [(.\) The Heart Rhythm UK Familial )] TJ ET
BT 26.250 530.691 Td /F1 9.8 Tf  [(Sudden Death Syndromes Statement Development Group published in 2008 a position statement on genetic testing for sudden )] TJ ET
BT 26.250 518.786 Td /F1 9.8 Tf  [(cardiac death syndromes based on a comprehensive review of English language publications, grading of the evidence, and )] TJ ET
BT 26.250 506.881 Td /F1 9.8 Tf  [(secondary review of the evidence by an external committee)] TJ ET
0.267 0.267 0.267 rg
BT 282.568 508.388 Td /F4 8.7 Tf  [(3)] TJ ET
0.271 0.267 0.267 rg
BT 287.386 506.881 Td /F1 9.8 Tf  [(. The Group followed with a position statement on ICD placement )] TJ ET
BT 26.250 494.976 Td /F1 9.8 Tf  [(for these conditions based on risk of SCD)] TJ ET
0.267 0.267 0.267 rg
BT 205.621 496.484 Td /F4 8.7 Tf  [(46)] TJ ET
0.271 0.267 0.267 rg
BT 215.258 494.976 Td /F1 9.8 Tf  [(. The first position statement and the more recent HRS/EHRA report recommend )] TJ ET
BT 26.250 483.072 Td /F1 9.8 Tf  [(genetic testing for all patients with a firm diagnosis of congenital LQTS and those with clinical features of CPVT \(due to its )] TJ ET
BT 26.250 471.167 Td /F1 9.8 Tf  [(severity, despite an acknowledged lower clinical sensitivity\), but that expert clinical and family history assessment are needed )] TJ ET
BT 26.250 459.262 Td /F1 9.8 Tf  [(when genetic testing is undertaken for borderline LQTS cases and known or suspected cases of BrS. Practice guidelines from )] TJ ET
BT 26.250 447.357 Td /F1 9.8 Tf  [(the American College of Cardiology / American Heart Association / European Society of Cardiology)] TJ ET
0.267 0.267 0.267 rg
BT 453.251 448.865 Td /F4 8.7 Tf  [(47)] TJ ET
0.271 0.267 0.267 rg
BT 462.889 447.357 Td /F1 9.8 Tf  [( have noted an evolving )] TJ ET
BT 26.250 435.453 Td /F1 9.8 Tf  [(role for genetic testing of LQTS in risk stratification and clinical decision making. Both independent reviews and professional )] TJ ET
BT 26.250 423.548 Td /F1 9.8 Tf  [(society guidelines agree that genetic testing by itself is not recommended in making a diagnosis or prognosis for BrS, though it )] TJ ET
BT 26.250 411.643 Td /F1 9.8 Tf  [(may be used to support clinical diagnosis, and early detection of at-risk relatives)] TJ ET
0.267 0.267 0.267 rg
BT 370.893 413.150 Td /F4 8.7 Tf  [(6)] TJ ET
BT 375.712 413.150 Td /F4 8.7 Tf  [(25)] TJ ET
BT 385.349 413.150 Td /F4 8.7 Tf  [(48)] TJ ET
0.271 0.267 0.267 rg
BT 394.986 411.643 Td /F1 9.8 Tf  [(. Several HRS / EHRA consensus )] TJ ET
BT 26.250 399.738 Td /F1 9.8 Tf  [(statements clarify that genetic testing can be useful in patients clinically suspected of having BrS with a type 1 \(�coved� ST )] TJ ET
BT 26.250 387.834 Td /F1 9.8 Tf  [(segment elevation\) ECG pattern, but that it is not indicated in the setting of an isolated type 2 \(less specific, �saddleback� ST )] TJ ET
BT 26.250 375.929 Td /F1 9.8 Tf  [(elevation\) or 3 \(either shape but less pronounced elevation\) pattern)] TJ ET
0.267 0.267 0.267 rg
BT 316.186 377.436 Td /F4 8.7 Tf  [(6)] TJ ET
BT 321.004 377.436 Td /F4 8.7 Tf  [(20)] TJ ET
BT 330.642 377.436 Td /F4 8.7 Tf  [(25)] TJ ET
0.271 0.267 0.267 rg
BT 340.279 375.929 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 339.326 Td /F4 12.0 Tf  [(Evidence Overview)] TJ ET
BT 26.250 319.372 Td /F5 9.8 Tf  [(Analytic Validity:)] TJ ET
BT 26.250 299.967 Td /F1 9.8 Tf  [(Commercially available channelopathy genetic testing \(CGT\) for LQTS, SQTS, CPVT, and BrS involves direct sequencing of )] TJ ET
BT 26.250 288.063 Td /F1 9.8 Tf  [(protein-coding portions and flanking regions of targeted exons following PCR amplification. Sequencing is performed in both )] TJ ET
BT 26.250 276.158 Td /F1 9.8 Tf  [(forward and reverse directions. Sequences are analyzed for heterozygous and homozygous variants using public reference )] TJ ET
BT 26.250 264.253 Td /F1 9.8 Tf  [(sequences)] TJ ET
0.267 0.267 0.267 rg
BT 73.401 265.760 Td /F4 8.7 Tf  [(17)] TJ ET
BT 83.038 265.760 Td /F4 8.7 Tf  [(41)] TJ ET
0.271 0.267 0.267 rg
BT 92.676 264.253 Td /F1 9.8 Tf  [(. For the FAMILION� test, variants detected in the initial analysis are confirmed by repeating the sequencing )] TJ ET
BT 26.250 252.348 Td /F1 9.8 Tf  [(twice in the forward and three times in the backward direction. Transgenomic reports a CGT error rate of < 1% )] TJ ET
0.267 0.267 0.267 rg
BT 503.912 253.856 Td /F4 8.7 Tf  [(17)] TJ ET
0.271 0.267 0.267 rg
BT 513.550 252.348 Td /F1 9.8 Tf  [(. GeneDx )] TJ ET
BT 26.250 240.444 Td /F1 9.8 Tf  [(indicates a 98% �technical sensitivity� for assessment of each of the four conditions)] TJ ET
0.267 0.267 0.267 rg
BT 384.445 241.951 Td /F4 8.7 Tf  [(18)] TJ ET
0.271 0.267 0.267 rg
BT 394.083 240.444 Td /F1 9.8 Tf  [(. The John Welsh Cardiovascular )] TJ ET
BT 26.250 228.539 Td /F1 9.8 Tf  [(Laboratory at Baylor College of Medicine makes available genetic diagnostic testing using DNA sequencing analysis for KCNJ2 )] TJ ET
BT 26.250 216.634 Td /F1 9.8 Tf  [(\(LQT7\) and CAV3 \(LQT9\) mutations. This facility reports approximately 99% detection of the exons that are sequenced)] TJ ET
0.267 0.267 0.267 rg
BT 539.432 218.141 Td /F4 8.7 Tf  [(49)] TJ ET
0.271 0.267 0.267 rg
BT 549.069 216.634 Td /F1 9.8 Tf  [(. )] TJ ET
BT 26.250 204.729 Td /F1 9.8 Tf  [(Failure to detect variants in the laboratory setting is attributed to refractoriness of the amplicon to analysis by direct DNA )] TJ ET
BT 26.250 192.825 Td /F1 9.8 Tf  [(sequencing or real-time PCR detection, sample mishandling, sample tracking errors, errors in data analysis, and other gene )] TJ ET
BT 26.250 180.920 Td /F1 9.8 Tf  [(specific issues \(see Clinical Validity\))] TJ ET
0.267 0.267 0.267 rg
BT 182.279 182.427 Td /F4 8.7 Tf  [(17)] TJ ET
0.271 0.267 0.267 rg
BT 191.917 180.920 Td /F1 9.8 Tf  [(. The FAMILION� analytic specificity approaches 100% for �Class I� \(deleterious or )] TJ ET
BT 26.250 169.015 Td /F1 9.8 Tf  [(probably deleterious\) mutations, and approximates 95% for �Class II� mutations \(of uncertain clinical significance � possibly )] TJ ET
BT 26.250 157.110 Td /F1 9.8 Tf  [(deleterious\))] TJ ET
0.267 0.267 0.267 rg
BT 77.184 158.618 Td /F4 8.7 Tf  [(41)] TJ ET
0.271 0.267 0.267 rg
BT 86.821 157.110 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 137.706 Td /F5 9.8 Tf  [(Clinical Validity:)] TJ ET
BT 26.250 118.301 Td /F1 9.8 Tf  [(The near perfect analytic sensitivities of these assays must be contrasted with the ability to detect genetic variants in the clinical )] TJ ET
BT 26.250 106.396 Td /F1 9.8 Tf  [(setting. The yield for the first 2,500 consecutive unrelated cases referred by physicians for commercially available long QT )] TJ ET
BT 26.250 94.491 Td /F1 9.8 Tf  [(syndrome genetic testing \(low-, intermediate-, and high-pretest probability\) was 36%; values in the literature range between 33 )] TJ ET
BT 26.250 82.587 Td /F1 9.8 Tf  [(and 39%)] TJ ET
0.267 0.267 0.267 rg
BT 64.733 84.094 Td /F4 8.7 Tf  [(50)] TJ ET
0.271 0.267 0.267 rg
BT 74.371 82.587 Td /F1 9.8 Tf  [(. Tester et al. reported greater yields of 72 to 78% using the 5 major LQTS genes for patients with the highest clinical )] TJ ET
BT 26.250 70.682 Td /F1 9.8 Tf  [(probability for LQTS \(Schwartz-Moss score >= 4 )] TJ ET
0.267 0.267 0.267 rg
BT 237.025 72.189 Td /F4 8.7 Tf  [(4)] TJ ET
0.271 0.267 0.267 rg
BT 241.844 70.682 Td /F1 9.8 Tf  [(\))] TJ ET
0.267 0.267 0.267 rg
BT 245.091 72.189 Td /F4 8.7 Tf  [(37)] TJ ET
0.271 0.267 0.267 rg
BT 254.728 70.682 Td /F1 9.8 Tf  [(. Transgenomic reports a 75 to 80% yield for such patients based upon )] TJ ET
BT 26.250 58.777 Td /F1 9.8 Tf  [(multiple data sets)] TJ ET
0.267 0.267 0.267 rg
BT 102.115 60.284 Td /F4 8.7 Tf  [(17)] TJ ET
BT 111.752 60.284 Td /F4 8.7 Tf  [(51)] TJ ET
0.271 0.267 0.267 rg
BT 121.389 58.777 Td /F1 9.8 Tf  [(. False negatives may be explained by a number of factors, including the existence of private mutations)] TJ ET
0.267 0.267 0.267 rg
BT 565.765 60.284 Td /F4 8.7 Tf  [(37)] TJ ET
0.271 0.267 0.267 rg
BT 575.403 58.777 Td /F1 9.8 Tf  [(, )] TJ ET
BT 26.250 46.872 Td /F1 9.8 Tf  [(the presence of non-targeted exons)] TJ ET
0.267 0.267 0.267 rg
BT 180.173 48.380 Td /F4 8.7 Tf  [(17)] TJ ET
0.271 0.267 0.267 rg
BT 189.811 46.872 Td /F1 9.8 Tf  [( and relevant introns outside tested splice sites)] TJ ET
0.267 0.267 0.267 rg
BT 391.948 48.380 Td /F4 8.7 Tf  [(16)] TJ ET
0.271 0.267 0.267 rg
BT 401.585 46.872 Td /F1 9.8 Tf  [(, and the existence of large deletion and )] TJ ET
Q
q
15.000 32.587 577.500 744.413 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F5 9.8 Tf  [(Recommendations by independent groups)] TJ ET
BT 26.250 748.071 Td /F1 9.8 Tf  [(Two independent reviews have concluded that genetic testing has diagnostic value, including for the identification of )] TJ ET
BT 26.250 736.167 Td /F1 9.8 Tf  [(asymptomatic heterozygotes, for all four syndromes; definitive prognostic value for LQTS and weak or contingent prognostic )] TJ ET
BT 26.250 724.262 Td /F1 9.8 Tf  [(value \(depending on the nature of the findings\) for CPVT and BrS; and practical value in the determination of therapy for LQTS )] TJ ET
BT 26.250 712.357 Td /F1 9.8 Tf  [(alone)] TJ ET
0.267 0.267 0.267 rg
BT 50.099 713.864 Td /F4 8.7 Tf  [(1)] TJ ET
BT 54.917 713.864 Td /F4 8.7 Tf  [(30)] TJ ET
0.271 0.267 0.267 rg
BT 64.555 712.357 Td /F1 9.8 Tf  [(. One of the teams also published an �evidence-based� genetic testing scoring system to compare the relative clinical )] TJ ET
BT 26.250 700.452 Td /F1 9.8 Tf  [(value of genetic testing over these conditions \(LQTS > CPVT > BrS > SQTS\))] TJ ET
0.267 0.267 0.267 rg
BT 357.633 701.960 Td /F4 8.7 Tf  [(44)] TJ ET
0.271 0.267 0.267 rg
BT 367.270 700.452 Td /F1 9.8 Tf  [(. SQTS�s low score is associated with paucity of )] TJ ET
BT 26.250 688.548 Td /F1 9.8 Tf  [(data, this condition having first been described in 2000)] TJ ET
0.267 0.267 0.267 rg
BT 261.459 690.055 Td /F4 8.7 Tf  [(15)] TJ ET
0.271 0.267 0.267 rg
BT 271.096 688.548 Td /F1 9.8 Tf  [(. Criteria on when to screen for each channelopathy, based on )] TJ ET
BT 26.250 676.643 Td /F1 9.8 Tf  [(consensus documents and primary literature from 1995 onward, are laid out by Tzou and Gerstenfeld)] TJ ET
0.267 0.267 0.267 rg
BT 462.485 678.150 Td /F4 8.7 Tf  [(15)] TJ ET
0.271 0.267 0.267 rg
BT 472.122 676.643 Td /F1 9.8 Tf  [(. This review concluded )] TJ ET
BT 26.250 664.738 Td /F1 9.8 Tf  [(that genetic testing can lead to genotype-specific therapy in the case of LQTS, and decisions about ICD placement for )] TJ ET
BT 26.250 652.833 Td /F1 9.8 Tf  [(malignant arrhythmias associated with CPVT and SQTS)] TJ ET
0.267 0.267 0.267 rg
BT 268.459 654.341 Td /F4 8.7 Tf  [(15)] TJ ET
0.271 0.267 0.267 rg
BT 278.097 652.833 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 633.429 Td /F5 9.8 Tf  [(Guidelines by independent groups)] TJ ET
BT 26.250 614.024 Td /F1 9.8 Tf  [(A 2007 consensus report by the U.S. National Heart, Lung, and Blood Institute and the Office of Rare Diseases on gene )] TJ ET
BT 26.250 602.119 Td /F1 9.8 Tf  [(mutations affecting ion channel function concluded that genetic testing for LQTS must be combined with clinical evaluation, and )] TJ ET
BT 26.250 590.214 Td /F1 9.8 Tf  [(noted lack of clarity in the proportion of SQTS cases that might be explained by the corresponding KCNH2, KCNJ2, and KCNQ1 )] TJ ET
BT 26.250 578.310 Td /F1 9.8 Tf  [(genes)] TJ ET
0.267 0.267 0.267 rg
BT 52.809 579.817 Td /F4 8.7 Tf  [(45)] TJ ET
0.271 0.267 0.267 rg
BT 62.446 578.310 Td /F1 9.8 Tf  [(. A 2011 Heart Rhythm Society \(HRS\) / European Heart Rhythm Association \(EHRA\) consensus statement further )] TJ ET
BT 26.250 566.405 Td /F1 9.8 Tf  [(states that LQTS genetic testing is recommended for any asymptomatic patient with idiopathic \(not attributable to QT prolonging )] TJ ET
BT 26.250 554.500 Td /F1 9.8 Tf  [(disease states or conditions\) QTc values > .48 s. \(prepuberty\) or > .50 s. \(adult\), and may be considered for QTc values >= .46 )] TJ ET
BT 26.250 542.595 Td /F1 9.8 Tf  [(and .48, respectively)] TJ ET
0.267 0.267 0.267 rg
BT 115.667 544.103 Td /F4 8.7 Tf  [(6)] TJ ET
0.271 0.267 0.267 rg
BT 120.486 542.595 Td /F1 9.8 Tf  [(. \(QTc = �heart rate-corrected QT interval,� as per the Bazett formula)] TJ ET
0.267 0.267 0.267 rg
BT 415.531 544.103 Td /F4 8.7 Tf  [(4)] TJ ET
0.271 0.267 0.267 rg
BT 420.349 542.595 Td /F1 9.8 Tf  [(.\) The Heart Rhythm UK Familial )] TJ ET
BT 26.250 530.691 Td /F1 9.8 Tf  [(Sudden Death Syndromes Statement Development Group published in 2008 a position statement on genetic testing for sudden )] TJ ET
BT 26.250 518.786 Td /F1 9.8 Tf  [(cardiac death syndromes based on a comprehensive review of English language publications, grading of the evidence, and )] TJ ET
BT 26.250 506.881 Td /F1 9.8 Tf  [(secondary review of the evidence by an external committee)] TJ ET
0.267 0.267 0.267 rg
BT 282.568 508.388 Td /F4 8.7 Tf  [(3)] TJ ET
0.271 0.267 0.267 rg
BT 287.386 506.881 Td /F1 9.8 Tf  [(. The Group followed with a position statement on ICD placement )] TJ ET
BT 26.250 494.976 Td /F1 9.8 Tf  [(for these conditions based on risk of SCD)] TJ ET
0.267 0.267 0.267 rg
BT 205.621 496.484 Td /F4 8.7 Tf  [(46)] TJ ET
0.271 0.267 0.267 rg
BT 215.258 494.976 Td /F1 9.8 Tf  [(. The first position statement and the more recent HRS/EHRA report recommend )] TJ ET
BT 26.250 483.072 Td /F1 9.8 Tf  [(genetic testing for all patients with a firm diagnosis of congenital LQTS and those with clinical features of CPVT \(due to its )] TJ ET
BT 26.250 471.167 Td /F1 9.8 Tf  [(severity, despite an acknowledged lower clinical sensitivity\), but that expert clinical and family history assessment are needed )] TJ ET
BT 26.250 459.262 Td /F1 9.8 Tf  [(when genetic testing is undertaken for borderline LQTS cases and known or suspected cases of BrS. Practice guidelines from )] TJ ET
BT 26.250 447.357 Td /F1 9.8 Tf  [(the American College of Cardiology / American Heart Association / European Society of Cardiology)] TJ ET
0.267 0.267 0.267 rg
BT 453.251 448.865 Td /F4 8.7 Tf  [(47)] TJ ET
0.271 0.267 0.267 rg
BT 462.889 447.357 Td /F1 9.8 Tf  [( have noted an evolving )] TJ ET
BT 26.250 435.453 Td /F1 9.8 Tf  [(role for genetic testing of LQTS in risk stratification and clinical decision making. Both independent reviews and professional )] TJ ET
BT 26.250 423.548 Td /F1 9.8 Tf  [(society guidelines agree that genetic testing by itself is not recommended in making a diagnosis or prognosis for BrS, though it )] TJ ET
BT 26.250 411.643 Td /F1 9.8 Tf  [(may be used to support clinical diagnosis, and early detection of at-risk relatives)] TJ ET
0.267 0.267 0.267 rg
BT 370.893 413.150 Td /F4 8.7 Tf  [(6)] TJ ET
BT 375.712 413.150 Td /F4 8.7 Tf  [(25)] TJ ET
BT 385.349 413.150 Td /F4 8.7 Tf  [(48)] TJ ET
0.271 0.267 0.267 rg
BT 394.986 411.643 Td /F1 9.8 Tf  [(. Several HRS / EHRA consensus )] TJ ET
BT 26.250 399.738 Td /F1 9.8 Tf  [(statements clarify that genetic testing can be useful in patients clinically suspected of having BrS with a type 1 \(�coved� ST )] TJ ET
BT 26.250 387.834 Td /F1 9.8 Tf  [(segment elevation\) ECG pattern, but that it is not indicated in the setting of an isolated type 2 \(less specific, �saddleback� ST )] TJ ET
BT 26.250 375.929 Td /F1 9.8 Tf  [(elevation\) or 3 \(either shape but less pronounced elevation\) pattern)] TJ ET
0.267 0.267 0.267 rg
BT 316.186 377.436 Td /F4 8.7 Tf  [(6)] TJ ET
BT 321.004 377.436 Td /F4 8.7 Tf  [(20)] TJ ET
BT 330.642 377.436 Td /F4 8.7 Tf  [(25)] TJ ET
0.271 0.267 0.267 rg
BT 340.279 375.929 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 339.326 Td /F4 12.0 Tf  [(Evidence Overview)] TJ ET
BT 26.250 319.372 Td /F5 9.8 Tf  [(Analytic Validity:)] TJ ET
BT 26.250 299.967 Td /F1 9.8 Tf  [(Commercially available channelopathy genetic testing \(CGT\) for LQTS, SQTS, CPVT, and BrS involves direct sequencing of )] TJ ET
BT 26.250 288.063 Td /F1 9.8 Tf  [(protein-coding portions and flanking regions of targeted exons following PCR amplification. Sequencing is performed in both )] TJ ET
BT 26.250 276.158 Td /F1 9.8 Tf  [(forward and reverse directions. Sequences are analyzed for heterozygous and homozygous variants using public reference )] TJ ET
BT 26.250 264.253 Td /F1 9.8 Tf  [(sequences)] TJ ET
0.267 0.267 0.267 rg
BT 73.401 265.760 Td /F4 8.7 Tf  [(17)] TJ ET
BT 83.038 265.760 Td /F4 8.7 Tf  [(41)] TJ ET
0.271 0.267 0.267 rg
BT 92.676 264.253 Td /F1 9.8 Tf  [(. For the FAMILION� test, variants detected in the initial analysis are confirmed by repeating the sequencing )] TJ ET
BT 26.250 252.348 Td /F1 9.8 Tf  [(twice in the forward and three times in the backward direction. Transgenomic reports a CGT error rate of < 1% )] TJ ET
0.267 0.267 0.267 rg
BT 503.912 253.856 Td /F4 8.7 Tf  [(17)] TJ ET
0.271 0.267 0.267 rg
BT 513.550 252.348 Td /F1 9.8 Tf  [(. GeneDx )] TJ ET
BT 26.250 240.444 Td /F1 9.8 Tf  [(indicates a 98% �technical sensitivity� for assessment of each of the four conditions)] TJ ET
0.267 0.267 0.267 rg
BT 384.445 241.951 Td /F4 8.7 Tf  [(18)] TJ ET
0.271 0.267 0.267 rg
BT 394.083 240.444 Td /F1 9.8 Tf  [(. The John Welsh Cardiovascular )] TJ ET
BT 26.250 228.539 Td /F1 9.8 Tf  [(Laboratory at Baylor College of Medicine makes available genetic diagnostic testing using DNA sequencing analysis for KCNJ2 )] TJ ET
BT 26.250 216.634 Td /F1 9.8 Tf  [(\(LQT7\) and CAV3 \(LQT9\) mutations. This facility reports approximately 99% detection of the exons that are sequenced)] TJ ET
0.267 0.267 0.267 rg
BT 539.432 218.141 Td /F4 8.7 Tf  [(49)] TJ ET
0.271 0.267 0.267 rg
BT 549.069 216.634 Td /F1 9.8 Tf  [(. )] TJ ET
BT 26.250 204.729 Td /F1 9.8 Tf  [(Failure to detect variants in the laboratory setting is attributed to refractoriness of the amplicon to analysis by direct DNA )] TJ ET
BT 26.250 192.825 Td /F1 9.8 Tf  [(sequencing or real-time PCR detection, sample mishandling, sample tracking errors, errors in data analysis, and other gene )] TJ ET
BT 26.250 180.920 Td /F1 9.8 Tf  [(specific issues \(see Clinical Validity\))] TJ ET
0.267 0.267 0.267 rg
BT 182.279 182.427 Td /F4 8.7 Tf  [(17)] TJ ET
0.271 0.267 0.267 rg
BT 191.917 180.920 Td /F1 9.8 Tf  [(. The FAMILION� analytic specificity approaches 100% for �Class I� \(deleterious or )] TJ ET
BT 26.250 169.015 Td /F1 9.8 Tf  [(probably deleterious\) mutations, and approximates 95% for �Class II� mutations \(of uncertain clinical significance � possibly )] TJ ET
BT 26.250 157.110 Td /F1 9.8 Tf  [(deleterious\))] TJ ET
0.267 0.267 0.267 rg
BT 77.184 158.618 Td /F4 8.7 Tf  [(41)] TJ ET
0.271 0.267 0.267 rg
BT 86.821 157.110 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 137.706 Td /F5 9.8 Tf  [(Clinical Validity:)] TJ ET
BT 26.250 118.301 Td /F1 9.8 Tf  [(The near perfect analytic sensitivities of these assays must be contrasted with the ability to detect genetic variants in the clinical )] TJ ET
BT 26.250 106.396 Td /F1 9.8 Tf  [(setting. The yield for the first 2,500 consecutive unrelated cases referred by physicians for commercially available long QT )] TJ ET
BT 26.250 94.491 Td /F1 9.8 Tf  [(syndrome genetic testing \(low-, intermediate-, and high-pretest probability\) was 36%; values in the literature range between 33 )] TJ ET
BT 26.250 82.587 Td /F1 9.8 Tf  [(and 39%)] TJ ET
0.267 0.267 0.267 rg
BT 64.733 84.094 Td /F4 8.7 Tf  [(50)] TJ ET
0.271 0.267 0.267 rg
BT 74.371 82.587 Td /F1 9.8 Tf  [(. Tester et al. reported greater yields of 72 to 78% using the 5 major LQTS genes for patients with the highest clinical )] TJ ET
BT 26.250 70.682 Td /F1 9.8 Tf  [(probability for LQTS \(Schwartz-Moss score >= 4 )] TJ ET
0.267 0.267 0.267 rg
BT 237.025 72.189 Td /F4 8.7 Tf  [(4)] TJ ET
0.271 0.267 0.267 rg
BT 241.844 70.682 Td /F1 9.8 Tf  [(\))] TJ ET
0.267 0.267 0.267 rg
BT 245.091 72.189 Td /F4 8.7 Tf  [(37)] TJ ET
0.271 0.267 0.267 rg
BT 254.728 70.682 Td /F1 9.8 Tf  [(. Transgenomic reports a 75 to 80% yield for such patients based upon )] TJ ET
BT 26.250 58.777 Td /F1 9.8 Tf  [(multiple data sets)] TJ ET
0.267 0.267 0.267 rg
BT 102.115 60.284 Td /F4 8.7 Tf  [(17)] TJ ET
BT 111.752 60.284 Td /F4 8.7 Tf  [(51)] TJ ET
0.271 0.267 0.267 rg
BT 121.389 58.777 Td /F1 9.8 Tf  [(. False negatives may be explained by a number of factors, including the existence of private mutations)] TJ ET
0.267 0.267 0.267 rg
BT 565.765 60.284 Td /F4 8.7 Tf  [(37)] TJ ET
0.271 0.267 0.267 rg
BT 575.403 58.777 Td /F1 9.8 Tf  [(, )] TJ ET
BT 26.250 46.872 Td /F1 9.8 Tf  [(the presence of non-targeted exons)] TJ ET
0.267 0.267 0.267 rg
BT 180.173 48.380 Td /F4 8.7 Tf  [(17)] TJ ET
0.271 0.267 0.267 rg
BT 189.811 46.872 Td /F1 9.8 Tf  [( and relevant introns outside tested splice sites)] TJ ET
0.267 0.267 0.267 rg
BT 391.948 48.380 Td /F4 8.7 Tf  [(16)] TJ ET
0.271 0.267 0.267 rg
BT 401.585 46.872 Td /F1 9.8 Tf  [(, and the existence of large deletion and )] TJ ET
Q
q
0.000 0.000 0.000 rg
BT 291.710 19.825 Td /F1 11.0 Tf  [(3)] TJ ET
BT 25.000 19.825 Td /F1 11.0 Tf  [(PLOS Currents Evidence on Genomic Tests)] TJ ET

Q
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0.271 0.267 0.267 rg
q
15.000 26.524 577.500 750.476 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F1 9.8 Tf  [(duplication mutations \(generally on the scale of a whole exon or more\))] TJ ET
0.267 0.267 0.267 rg
BT 329.173 768.983 Td /F4 8.7 Tf  [(7)] TJ ET
BT 333.991 768.983 Td /F4 8.7 Tf  [(17)] TJ ET
0.271 0.267 0.267 rg
BT 343.629 767.476 Td /F1 9.8 Tf  [(. LQTS is in the upper range among cardiac )] TJ ET
BT 26.250 755.571 Td /F1 9.8 Tf  [(conditions in terms of number of affected genes \(13\) and allelic mutations \(>800\) while BrS lies in the midrange \(8 genes and )] TJ ET
BT 26.250 743.667 Td /F1 9.8 Tf  [(>400 allelic mutations\). By comparison, current compendia of arrhythmogenic right ventricular dysplasia/cardiomyopathy list 9 )] TJ ET
BT 26.250 731.762 Td /F1 9.8 Tf  [(affected genes and >400 allelic mutations, while Marfan syndrome has ~600 allelic mutations in the FBN1 fibrillin gene.)] TJ ET
BT 26.250 712.357 Td /F1 9.8 Tf  [(Authors have reported various mutational hotspots in the case of LQTS arising either independently or due to founder effects, )] TJ ET
BT 26.250 700.452 Td /F1 9.8 Tf  [(which because of their severity may aid risk stratification)] TJ ET
0.267 0.267 0.267 rg
BT 268.996 701.960 Td /F4 8.7 Tf  [(21)] TJ ET
0.271 0.267 0.267 rg
BT 278.633 700.452 Td /F1 9.8 Tf  [(. Interpretation of results for probands and family members is )] TJ ET
BT 26.250 688.548 Td /F1 9.8 Tf  [(complicated by variable penetrance in family members with the same genotype)] TJ ET
0.267 0.267 0.267 rg
BT 367.091 690.055 Td /F4 8.7 Tf  [(52)] TJ ET
0.271 0.267 0.267 rg
BT 376.728 688.548 Td /F1 9.8 Tf  [(, and the possibility of compound mutations, )] TJ ET
BT 26.250 676.643 Td /F1 9.8 Tf  [(observed in 4 to 10% of mutation positive individuals)] TJ ET
0.267 0.267 0.267 rg
BT 252.772 678.150 Td /F4 8.7 Tf  [(37)] TJ ET
BT 262.409 678.150 Td /F4 8.7 Tf  [(50)] TJ ET
BT 272.046 678.150 Td /F4 8.7 Tf  [(53)] TJ ET
BT 281.684 678.150 Td /F4 8.7 Tf  [(54)] TJ ET
0.271 0.267 0.267 rg
BT 291.321 676.643 Td /F1 9.8 Tf  [(. Estimated positive predictive values \(EPV � percent of mutations )] TJ ET
BT 26.250 664.738 Td /F1 9.8 Tf  [(found in definite cases that would cause the condition\) for LQTS genetic testing based on an assessment of > 1300 unrelated )] TJ ET
BT 26.250 652.833 Td /F1 9.8 Tf  [(index cases with Schwartz score >= 4 or QTc >= .48 s. are: 96% \(95% C.I., 94-98\) for )] TJ ET
BT 397.998 652.833 Td /F5 9.8 Tf  [(KCNQ1)] TJ ET
BT 431.587 652.833 Td /F1 9.8 Tf  [(; 93% \(89-95\) for )] TJ ET
BT 507.452 652.833 Td /F5 9.8 Tf  [(KCNH2)] TJ ET
BT 540.494 652.833 Td /F1 9.8 Tf  [(; and )] TJ ET
BT 26.250 640.929 Td /F1 9.8 Tf  [(63% \(40-77\) for )] TJ ET
BT 96.694 640.929 Td /F5 9.8 Tf  [(SCN5A)] TJ ET
0.267 0.267 0.267 rg
BT 129.200 642.436 Td /F4 8.7 Tf  [(55)] TJ ET
0.271 0.267 0.267 rg
BT 138.838 640.929 Td /F1 9.8 Tf  [(. Nonmissense mutations have an EPV > 99% regardless of location)] TJ ET
0.267 0.267 0.267 rg
BT 433.912 642.436 Td /F4 8.7 Tf  [(55)] TJ ET
0.271 0.267 0.267 rg
BT 443.549 640.929 Td /F1 9.8 Tf  [(. EPVs for missense mutations )] TJ ET
BT 26.250 629.024 Td /F1 9.8 Tf  [(range from 0% in the interdomain linker of )] TJ ET
BT 209.950 629.024 Td /F5 9.8 Tf  [(SCN5A)] TJ ET
BT 242.456 629.024 Td /F1 9.8 Tf  [( to 100% in the transmembrane/linker/pore regions of )] TJ ET
BT 474.935 629.024 Td /F5 9.8 Tf  [(KCNH2)] TJ ET
BT 507.978 629.024 Td /F1 9.8 Tf  [(. Similar figures )] TJ ET
BT 26.250 617.119 Td /F1 9.8 Tf  [(are lacking for the other channelopathies.)] TJ ET
BT 26.250 597.714 Td /F1 9.8 Tf  [(Several groups have investigated ECG genotyping \(to be distinguished from use in initial diagnosis\) through T-wave )] TJ ET
BT 26.250 585.810 Td /F1 9.8 Tf  [(morphology as a means of reducing the cost of LQTS mutational genotyping)] TJ ET
0.267 0.267 0.267 rg
BT 355.205 587.317 Td /F4 8.7 Tf  [(56)] TJ ET
BT 364.843 587.317 Td /F4 8.7 Tf  [(57)] TJ ET
BT 374.480 587.317 Td /F4 8.7 Tf  [(58)] TJ ET
0.271 0.267 0.267 rg
BT 384.117 585.810 Td /F1 9.8 Tf  [(. Sensitivity is highly dependent on the gene )] TJ ET
BT 26.250 573.905 Td /F1 9.8 Tf  [(being assessed, and varies between 92% \(LQT2\) and 47% \(LQT3\))] TJ ET
0.267 0.267 0.267 rg
BT 314.548 575.412 Td /F4 8.7 Tf  [(57)] TJ ET
BT 324.185 575.412 Td /F4 8.7 Tf  [(58)] TJ ET
0.271 0.267 0.267 rg
BT 333.822 573.905 Td /F1 9.8 Tf  [(. QTc interval alone lacks predictive value for genotyping)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 563.507 Td /F4 8.7 Tf  [(56)] TJ ET
BT 35.887 563.507 Td /F4 8.7 Tf  [(57)] TJ ET
0.271 0.267 0.267 rg
BT 45.525 562.000 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 542.595 Td /F1 9.8 Tf  [(For channelopathy genetic testing \(CGT\) of the other inherited arrhythmia syndromes, Transgenomic reports a clinical )] TJ ET
BT 26.250 530.691 Td /F1 9.8 Tf  [(sensitivity of 65-75% \(CPVT\), 25-40% \(BrS\), and 15-20% \(SQTS\))] TJ ET
0.267 0.267 0.267 rg
BT 309.088 532.198 Td /F4 8.7 Tf  [(17)] TJ ET
0.271 0.267 0.267 rg
BT 318.725 530.691 Td /F1 9.8 Tf  [(. GeneDx)] TJ ET
0.267 0.267 0.267 rg
BT 359.909 532.198 Td /F4 8.7 Tf  [(18)] TJ ET
0.271 0.267 0.267 rg
BT 369.546 530.691 Td /F1 9.8 Tf  [( and the Correlagen CardioGeneScan�)] TJ ET
0.267 0.267 0.267 rg
BT 540.396 532.198 Td /F4 8.7 Tf  [(59)] TJ ET
0.271 0.267 0.267 rg
BT 550.033 530.691 Td /F1 9.8 Tf  [( also )] TJ ET
BT 26.250 518.786 Td /F1 9.8 Tf  [(test for these conditions. The GeneDx and Correlagen test information / FAQ sheets provide rough estimates of clinical )] TJ ET
BT 26.250 506.881 Td /F1 9.8 Tf  [(sensitivity; figures from Correlagen are also reported with the assays. Some commercial laboratories only provide CPVT )] TJ ET
BT 26.250 494.976 Td /F1 9.8 Tf  [(screening of a limited number of select exons encompassing critical )] TJ ET
BT 320.486 494.976 Td /F5 9.8 Tf  [(RYR2)] TJ ET
BT 346.489 494.976 Td /F1 9.8 Tf  [( regions, which can contribute to false negatives)] TJ ET
0.267 0.267 0.267 rg
BT 554.047 496.484 Td /F4 8.7 Tf  [(30)] TJ ET
0.271 0.267 0.267 rg
BT 563.684 494.976 Td /F1 9.8 Tf  [(. )] TJ ET
BT 26.250 483.072 Td /F1 9.8 Tf  [(Disagreement exists on the impact of combining other variables with mutational results in order to increase clinical sensitivity; )] TJ ET
BT 26.250 471.167 Td /F1 9.8 Tf  [(results vary by arrhythmia syndrome, genotype, and size of the study population)] TJ ET
0.267 0.267 0.267 rg
BT 371.449 472.674 Td /F4 8.7 Tf  [(10)] TJ ET
BT 381.086 472.674 Td /F4 8.7 Tf  [(27)] TJ ET
BT 390.723 472.674 Td /F4 8.7 Tf  [(60)] TJ ET
0.271 0.267 0.267 rg
BT 400.361 471.167 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 451.762 Td /F1 9.8 Tf  [(Mutational analysis of 27 )] TJ ET
BT 136.259 451.762 Td /F5 9.8 Tf  [(SCN5A)] TJ ET
BT 168.766 451.762 Td /F1 9.8 Tf  [( exons on cases from BrS databases at 9 international centers resulted in yields of 11-28%)] TJ ET
0.267 0.267 0.267 rg
BT 560.033 453.269 Td /F4 8.7 Tf  [(35)] TJ ET
BT 569.671 453.269 Td /F4 8.7 Tf  [(43)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 439.857 Td /F1 9.8 Tf  [(, lower than the 25-40% figure Transgenomic reports)] TJ ET
0.267 0.267 0.267 rg
BT 253.844 441.365 Td /F4 8.7 Tf  [(17)] TJ ET
BT 263.482 441.365 Td /F4 8.7 Tf  [(43)] TJ ET
BT 273.119 441.365 Td /F4 8.7 Tf  [(60)] TJ ET
0.271 0.267 0.267 rg
BT 282.756 439.857 Td /F1 9.8 Tf  [(. The literature suggests that for BrS about a quarter of the patients )] TJ ET
BT 26.250 427.953 Td /F1 9.8 Tf  [(or fewer carry an )] TJ ET
BT 102.105 427.953 Td /F5 9.8 Tf  [(SCN5A)] TJ ET
BT 134.612 427.953 Td /F1 9.8 Tf  [( mutation \(commercial assays also include other lower frequency mutations\))] TJ ET
0.267 0.267 0.267 rg
BT 462.426 429.460 Td /F4 8.7 Tf  [(1)] TJ ET
BT 467.245 429.460 Td /F4 8.7 Tf  [(2)] TJ ET
BT 472.063 429.460 Td /F4 8.7 Tf  [(25)] TJ ET
0.271 0.267 0.267 rg
BT 481.701 427.953 Td /F1 9.8 Tf  [(. The low clinical )] TJ ET
BT 26.250 416.048 Td /F1 9.8 Tf  [(sensitivity of genetic testing for Brugada syndrome, due to the low gene frequency for the most prevalent type of mutation )] TJ ET
BT 26.250 404.143 Td /F1 9.8 Tf  [(\(involving )] TJ ET
BT 70.135 404.143 Td /F5 9.8 Tf  [(SCN5A)] TJ ET
BT 102.641 404.143 Td /F1 9.8 Tf  [(\), incompleteness of known allelic variants, and the role of an organic substrate in many cases, limits its )] TJ ET
BT 26.250 392.238 Td /F1 9.8 Tf  [(diagnostic capability)] TJ ET
0.267 0.267 0.267 rg
BT 113.493 393.746 Td /F4 8.7 Tf  [(15)] TJ ET
BT 123.130 393.746 Td /F4 8.7 Tf  [(61)] TJ ET
BT 132.768 393.746 Td /F4 8.7 Tf  [(62)] TJ ET
0.271 0.267 0.267 rg
BT 142.405 392.238 Td /F1 9.8 Tf  [(. Genetic testing for BrS is more often used for confirmatory purposes)] TJ ET
0.267 0.267 0.267 rg
BT 442.071 393.746 Td /F4 8.7 Tf  [(1)] TJ ET
0.271 0.267 0.267 rg
BT 446.890 392.238 Td /F1 9.8 Tf  [(. Higher yields for the various )] TJ ET
BT 26.250 380.334 Td /F1 9.8 Tf  [(channelopathies accrue in families with at least one recorded case of sudden unexpected death, permitting detection of )] TJ ET
BT 26.250 368.429 Td /F1 9.8 Tf  [(potentially affected relatives)] TJ ET
0.267 0.267 0.267 rg
BT 146.555 369.936 Td /F4 8.7 Tf  [(24)] TJ ET
0.271 0.267 0.267 rg
BT 156.193 368.429 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 349.024 Td /F5 9.8 Tf  [(Clinical Utility:)] TJ ET
BT 26.250 329.619 Td /F1 9.8 Tf  [(Genetic analysis has been found useful in risk stratification of LQTS patients and detection of at-risk family members, though )] TJ ET
BT 26.250 317.715 Td /F1 9.8 Tf  [(current knowledge of CPVT genetic variants does not in itself does not yield prognostic information)] TJ ET
0.267 0.267 0.267 rg
BT 451.106 319.222 Td /F4 8.7 Tf  [(15)] TJ ET
BT 460.744 319.222 Td /F4 8.7 Tf  [(22)] TJ ET
BT 470.381 319.222 Td /F4 8.7 Tf  [(27)] TJ ET
BT 480.018 319.222 Td /F4 8.7 Tf  [(30)] TJ ET
BT 489.656 319.222 Td /F4 8.7 Tf  [(36)] TJ ET
BT 499.293 319.222 Td /F4 8.7 Tf  [(41)] TJ ET
BT 508.930 319.222 Td /F4 8.7 Tf  [(48)] TJ ET
0.271 0.267 0.267 rg
BT 518.568 317.715 Td /F1 9.8 Tf  [(. �Intragenic )] TJ ET
BT 26.250 305.810 Td /F1 9.8 Tf  [(risk stratification� based on mutation type and location, and cellular function, particularly for the LQT1 and 2 genotypes, has )] TJ ET
BT 26.250 293.905 Td /F1 9.8 Tf  [(been an increasing part of large scale studies but is not yet in widespread practice)] TJ ET
0.267 0.267 0.267 rg
BT 380.126 295.412 Td /F4 8.7 Tf  [(1)] TJ ET
BT 384.945 295.412 Td /F4 8.7 Tf  [(6)] TJ ET
BT 389.764 295.412 Td /F4 8.7 Tf  [(11)] TJ ET
BT 399.401 295.412 Td /F4 8.7 Tf  [(41)] TJ ET
BT 409.038 295.412 Td /F4 8.7 Tf  [(47)] TJ ET
BT 418.676 295.412 Td /F4 8.7 Tf  [(63)] TJ ET
0.271 0.267 0.267 rg
BT 428.313 293.905 Td /F1 9.8 Tf  [(. A meta-analysis of 30 Brugada )] TJ ET
BT 26.250 282.000 Td /F1 9.8 Tf  [(syndrome prospective studies by Gehi et al.)] TJ ET
0.267 0.267 0.267 rg
BT 215.371 283.508 Td /F4 8.7 Tf  [(64)] TJ ET
0.271 0.267 0.267 rg
BT 225.008 282.000 Td /F1 9.8 Tf  [( concluded family history of SCD and presence of an )] TJ ET
BT 454.777 282.000 Td /F5 9.8 Tf  [(SCN5A)] TJ ET
BT 487.283 282.000 Td /F1 9.8 Tf  [( mutation by )] TJ ET
BT 26.250 270.096 Td /F1 9.8 Tf  [(themselves are insufficient to predict risk for cardiac events in BrS. Instead, debates about risk stratification for patients with this )] TJ ET
BT 26.250 258.191 Td /F1 9.8 Tf  [(condition have taken place largely on the electrocardiographic front)] TJ ET
0.267 0.267 0.267 rg
BT 315.640 259.698 Td /F4 8.7 Tf  [(65)] TJ ET
0.271 0.267 0.267 rg
BT 325.277 258.191 Td /F1 9.8 Tf  [(. The presence of spontaneous ST-segment elevation, )] TJ ET
BT 26.250 246.286 Td /F1 9.8 Tf  [(particularly with a type-1 pattern, in conjunction with a history of syncope remains the strongest predictor of BrS risk)] TJ ET
0.267 0.267 0.267 rg
BT 523.695 247.793 Td /F4 8.7 Tf  [(2)] TJ ET
0.271 0.267 0.267 rg
BT 528.514 246.286 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 226.881 Td /F1 9.8 Tf  [(Mutational information can serve as an adjunct to clinical and phenotypic assessment of genotype in therapeutic decisions for )] TJ ET
BT 26.250 214.977 Td /F1 9.8 Tf  [(LQTS)] TJ ET
0.267 0.267 0.267 rg
BT 51.717 216.484 Td /F4 8.7 Tf  [(30)] TJ ET
BT 61.354 216.484 Td /F4 8.7 Tf  [(36)] TJ ET
BT 70.992 216.484 Td /F4 8.7 Tf  [(48)] TJ ET
0.271 0.267 0.267 rg
BT 80.629 214.977 Td /F1 9.8 Tf  [(, though this role is not without controversy)] TJ ET
0.267 0.267 0.267 rg
BT 265.421 216.484 Td /F4 8.7 Tf  [(10)] TJ ET
BT 275.058 216.484 Td /F4 8.7 Tf  [(12)] TJ ET
BT 284.695 216.484 Td /F4 8.7 Tf  [(16)] TJ ET
BT 294.333 216.484 Td /F4 8.7 Tf  [(41)] TJ ET
BT 303.970 216.484 Td /F4 8.7 Tf  [(66)] TJ ET
0.271 0.267 0.267 rg
BT 313.607 214.977 Td /F1 9.8 Tf  [(. Clear evidence exists for genotype-specific therapy in )] TJ ET
BT 26.250 203.072 Td /F1 9.8 Tf  [(management of the LQT1, 2, and 3 genotypes, but it is less substantiated for the other LQTS genotypes due to their rarity)] TJ ET
0.267 0.267 0.267 rg
BT 549.786 204.579 Td /F4 8.7 Tf  [(11)] TJ ET
BT 559.423 204.579 Td /F4 8.7 Tf  [(12)] TJ ET
BT 569.061 204.579 Td /F4 8.7 Tf  [(13)] TJ ET
BT 26.250 192.674 Td /F4 8.7 Tf  [(36)] TJ ET
BT 35.887 192.674 Td /F4 8.7 Tf  [(67)] TJ ET
BT 45.525 192.674 Td /F4 8.7 Tf  [(68)] TJ ET
0.271 0.267 0.267 rg
BT 55.162 191.167 Td /F1 9.8 Tf  [(. Disagreement exists on the use of intragenic, site-specific information to predict actual clinical phenotype or response to )] TJ ET
BT 26.250 179.262 Td /F1 9.8 Tf  [(therapy for the LQTS genotypes)] TJ ET
0.267 0.267 0.267 rg
BT 164.993 180.770 Td /F4 8.7 Tf  [(11)] TJ ET
BT 174.630 180.770 Td /F4 8.7 Tf  [(37)] TJ ET
0.271 0.267 0.267 rg
BT 184.267 179.262 Td /F1 9.8 Tf  [(. In analyzing retrospective data on 27 of 128 LQTS patients in the 3 to 13 year-old age )] TJ ET
BT 26.250 167.358 Td /F1 9.8 Tf  [(range who received either pacemakers or ICDs as therapy, investigators in a 3-area study \(Utah, British Columbia, and Arizona\) )] TJ ET
BT 26.250 155.453 Td /F1 9.8 Tf  [(found no association between device placement decisions and implementation of genetic testing. However, the authors also )] TJ ET
BT 26.250 143.548 Td /F1 9.8 Tf  [(noted that all patients with )] TJ ET
BT 141.690 143.548 Td /F5 9.8 Tf  [(SCN5A)] TJ ET
BT 174.197 143.548 Td /F1 9.8 Tf  [( \(LQT3\) mutations had therapeutic devices, though only 1 of 30 with a )] TJ ET
BT 477.685 143.548 Td /F5 9.8 Tf  [(KCNQ1)] TJ ET
BT 511.274 143.548 Td /F1 9.8 Tf  [( \(LQT1\) )] TJ ET
BT 26.250 131.643 Td /F1 9.8 Tf  [(mutation had one)] TJ ET
0.267 0.267 0.267 rg
BT 101.588 133.151 Td /F4 8.7 Tf  [(69)] TJ ET
0.271 0.267 0.267 rg
BT 111.226 131.643 Td /F1 9.8 Tf  [(. The use of genetic testing in therapeutic decision making for the other inherited arrhythmia syndromes is )] TJ ET
BT 26.250 119.739 Td /F1 9.8 Tf  [(not yet substantiated but appears promising)] TJ ET
0.267 0.267 0.267 rg
BT 215.390 121.246 Td /F4 8.7 Tf  [(16)] TJ ET
BT 225.028 121.246 Td /F4 8.7 Tf  [(30)] TJ ET
BT 234.665 121.246 Td /F4 8.7 Tf  [(48)] TJ ET
BT 244.302 121.246 Td /F4 8.7 Tf  [(70)] TJ ET
0.271 0.267 0.267 rg
BT 253.940 119.739 Td /F1 9.8 Tf  [(. ECG remains the principal tool for BrS diagnosis and therapeutic follow-up)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 109.341 Td /F4 8.7 Tf  [(2)] TJ ET
BT 31.069 109.341 Td /F4 8.7 Tf  [(16)] TJ ET
BT 40.706 109.341 Td /F4 8.7 Tf  [(25)] TJ ET
0.271 0.267 0.267 rg
BT 50.343 107.834 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 88.429 Td /F1 9.8 Tf  [(Several teams have evaluated step-wise or tiered strategies also including phenotypic assessment to increase the efficiency of )] TJ ET
BT 26.250 76.524 Td /F1 9.8 Tf  [(LQTS and CPVT genetic testing)] TJ ET
0.267 0.267 0.267 rg
BT 164.983 78.032 Td /F4 8.7 Tf  [(1)] TJ ET
BT 169.801 78.032 Td /F4 8.7 Tf  [(7)] TJ ET
BT 174.620 78.032 Td /F4 8.7 Tf  [(53)] TJ ET
BT 184.257 78.032 Td /F4 8.7 Tf  [(71)] TJ ET
BT 193.895 78.032 Td /F4 8.7 Tf  [(72)] TJ ET
0.271 0.267 0.267 rg
BT 203.532 76.524 Td /F1 9.8 Tf  [(. Targeted screening based on phenotypic information can lower the cost of more )] TJ ET
BT 26.250 64.620 Td /F1 9.8 Tf  [(comprehensive LQTS genetic testing by ~60% )] TJ ET
0.267 0.267 0.267 rg
BT 229.742 66.127 Td /F4 8.7 Tf  [(71)] TJ ET
0.271 0.267 0.267 rg
BT 239.380 64.620 Td /F1 9.8 Tf  [(. Phillips et al. found LQTS genetic testing more cost-effective than not testing )] TJ ET
BT 26.250 52.715 Td /F1 9.8 Tf  [(for symptomatic index cases at an estimated cost of $2,500 per year of life saved \($50,000 per year of life saved is often used )] TJ ET
BT 26.250 40.810 Td /F1 9.8 Tf  [(as a standard threshold\))] TJ ET
0.267 0.267 0.267 rg
BT 131.384 42.317 Td /F4 8.7 Tf  [(73)] TJ ET
BT 141.022 42.317 Td /F4 8.7 Tf  [(74)] TJ ET
0.271 0.267 0.267 rg
BT 150.659 40.810 Td /F1 9.8 Tf  [(. Bai et al., in looking at 546 patients referred to a large consortium of LQTS research laboratories, )] TJ ET
Q
q
15.000 26.524 577.500 750.476 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F1 9.8 Tf  [(duplication mutations \(generally on the scale of a whole exon or more\))] TJ ET
0.267 0.267 0.267 rg
BT 329.173 768.983 Td /F4 8.7 Tf  [(7)] TJ ET
BT 333.991 768.983 Td /F4 8.7 Tf  [(17)] TJ ET
0.271 0.267 0.267 rg
BT 343.629 767.476 Td /F1 9.8 Tf  [(. LQTS is in the upper range among cardiac )] TJ ET
BT 26.250 755.571 Td /F1 9.8 Tf  [(conditions in terms of number of affected genes \(13\) and allelic mutations \(>800\) while BrS lies in the midrange \(8 genes and )] TJ ET
BT 26.250 743.667 Td /F1 9.8 Tf  [(>400 allelic mutations\). By comparison, current compendia of arrhythmogenic right ventricular dysplasia/cardiomyopathy list 9 )] TJ ET
BT 26.250 731.762 Td /F1 9.8 Tf  [(affected genes and >400 allelic mutations, while Marfan syndrome has ~600 allelic mutations in the FBN1 fibrillin gene.)] TJ ET
BT 26.250 712.357 Td /F1 9.8 Tf  [(Authors have reported various mutational hotspots in the case of LQTS arising either independently or due to founder effects, )] TJ ET
BT 26.250 700.452 Td /F1 9.8 Tf  [(which because of their severity may aid risk stratification)] TJ ET
0.267 0.267 0.267 rg
BT 268.996 701.960 Td /F4 8.7 Tf  [(21)] TJ ET
0.271 0.267 0.267 rg
BT 278.633 700.452 Td /F1 9.8 Tf  [(. Interpretation of results for probands and family members is )] TJ ET
BT 26.250 688.548 Td /F1 9.8 Tf  [(complicated by variable penetrance in family members with the same genotype)] TJ ET
0.267 0.267 0.267 rg
BT 367.091 690.055 Td /F4 8.7 Tf  [(52)] TJ ET
0.271 0.267 0.267 rg
BT 376.728 688.548 Td /F1 9.8 Tf  [(, and the possibility of compound mutations, )] TJ ET
BT 26.250 676.643 Td /F1 9.8 Tf  [(observed in 4 to 10% of mutation positive individuals)] TJ ET
0.267 0.267 0.267 rg
BT 252.772 678.150 Td /F4 8.7 Tf  [(37)] TJ ET
BT 262.409 678.150 Td /F4 8.7 Tf  [(50)] TJ ET
BT 272.046 678.150 Td /F4 8.7 Tf  [(53)] TJ ET
BT 281.684 678.150 Td /F4 8.7 Tf  [(54)] TJ ET
0.271 0.267 0.267 rg
BT 291.321 676.643 Td /F1 9.8 Tf  [(. Estimated positive predictive values \(EPV � percent of mutations )] TJ ET
BT 26.250 664.738 Td /F1 9.8 Tf  [(found in definite cases that would cause the condition\) for LQTS genetic testing based on an assessment of > 1300 unrelated )] TJ ET
BT 26.250 652.833 Td /F1 9.8 Tf  [(index cases with Schwartz score >= 4 or QTc >= .48 s. are: 96% \(95% C.I., 94-98\) for )] TJ ET
BT 397.998 652.833 Td /F5 9.8 Tf  [(KCNQ1)] TJ ET
BT 431.587 652.833 Td /F1 9.8 Tf  [(; 93% \(89-95\) for )] TJ ET
BT 507.452 652.833 Td /F5 9.8 Tf  [(KCNH2)] TJ ET
BT 540.494 652.833 Td /F1 9.8 Tf  [(; and )] TJ ET
BT 26.250 640.929 Td /F1 9.8 Tf  [(63% \(40-77\) for )] TJ ET
BT 96.694 640.929 Td /F5 9.8 Tf  [(SCN5A)] TJ ET
0.267 0.267 0.267 rg
BT 129.200 642.436 Td /F4 8.7 Tf  [(55)] TJ ET
0.271 0.267 0.267 rg
BT 138.838 640.929 Td /F1 9.8 Tf  [(. Nonmissense mutations have an EPV > 99% regardless of location)] TJ ET
0.267 0.267 0.267 rg
BT 433.912 642.436 Td /F4 8.7 Tf  [(55)] TJ ET
0.271 0.267 0.267 rg
BT 443.549 640.929 Td /F1 9.8 Tf  [(. EPVs for missense mutations )] TJ ET
BT 26.250 629.024 Td /F1 9.8 Tf  [(range from 0% in the interdomain linker of )] TJ ET
BT 209.950 629.024 Td /F5 9.8 Tf  [(SCN5A)] TJ ET
BT 242.456 629.024 Td /F1 9.8 Tf  [( to 100% in the transmembrane/linker/pore regions of )] TJ ET
BT 474.935 629.024 Td /F5 9.8 Tf  [(KCNH2)] TJ ET
BT 507.978 629.024 Td /F1 9.8 Tf  [(. Similar figures )] TJ ET
BT 26.250 617.119 Td /F1 9.8 Tf  [(are lacking for the other channelopathies.)] TJ ET
BT 26.250 597.714 Td /F1 9.8 Tf  [(Several groups have investigated ECG genotyping \(to be distinguished from use in initial diagnosis\) through T-wave )] TJ ET
BT 26.250 585.810 Td /F1 9.8 Tf  [(morphology as a means of reducing the cost of LQTS mutational genotyping)] TJ ET
0.267 0.267 0.267 rg
BT 355.205 587.317 Td /F4 8.7 Tf  [(56)] TJ ET
BT 364.843 587.317 Td /F4 8.7 Tf  [(57)] TJ ET
BT 374.480 587.317 Td /F4 8.7 Tf  [(58)] TJ ET
0.271 0.267 0.267 rg
BT 384.117 585.810 Td /F1 9.8 Tf  [(. Sensitivity is highly dependent on the gene )] TJ ET
BT 26.250 573.905 Td /F1 9.8 Tf  [(being assessed, and varies between 92% \(LQT2\) and 47% \(LQT3\))] TJ ET
0.267 0.267 0.267 rg
BT 314.548 575.412 Td /F4 8.7 Tf  [(57)] TJ ET
BT 324.185 575.412 Td /F4 8.7 Tf  [(58)] TJ ET
0.271 0.267 0.267 rg
BT 333.822 573.905 Td /F1 9.8 Tf  [(. QTc interval alone lacks predictive value for genotyping)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 563.507 Td /F4 8.7 Tf  [(56)] TJ ET
BT 35.887 563.507 Td /F4 8.7 Tf  [(57)] TJ ET
0.271 0.267 0.267 rg
BT 45.525 562.000 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 542.595 Td /F1 9.8 Tf  [(For channelopathy genetic testing \(CGT\) of the other inherited arrhythmia syndromes, Transgenomic reports a clinical )] TJ ET
BT 26.250 530.691 Td /F1 9.8 Tf  [(sensitivity of 65-75% \(CPVT\), 25-40% \(BrS\), and 15-20% \(SQTS\))] TJ ET
0.267 0.267 0.267 rg
BT 309.088 532.198 Td /F4 8.7 Tf  [(17)] TJ ET
0.271 0.267 0.267 rg
BT 318.725 530.691 Td /F1 9.8 Tf  [(. GeneDx)] TJ ET
0.267 0.267 0.267 rg
BT 359.909 532.198 Td /F4 8.7 Tf  [(18)] TJ ET
0.271 0.267 0.267 rg
BT 369.546 530.691 Td /F1 9.8 Tf  [( and the Correlagen CardioGeneScan�)] TJ ET
0.267 0.267 0.267 rg
BT 540.396 532.198 Td /F4 8.7 Tf  [(59)] TJ ET
0.271 0.267 0.267 rg
BT 550.033 530.691 Td /F1 9.8 Tf  [( also )] TJ ET
BT 26.250 518.786 Td /F1 9.8 Tf  [(test for these conditions. The GeneDx and Correlagen test information / FAQ sheets provide rough estimates of clinical )] TJ ET
BT 26.250 506.881 Td /F1 9.8 Tf  [(sensitivity; figures from Correlagen are also reported with the assays. Some commercial laboratories only provide CPVT )] TJ ET
BT 26.250 494.976 Td /F1 9.8 Tf  [(screening of a limited number of select exons encompassing critical )] TJ ET
BT 320.486 494.976 Td /F5 9.8 Tf  [(RYR2)] TJ ET
BT 346.489 494.976 Td /F1 9.8 Tf  [( regions, which can contribute to false negatives)] TJ ET
0.267 0.267 0.267 rg
BT 554.047 496.484 Td /F4 8.7 Tf  [(30)] TJ ET
0.271 0.267 0.267 rg
BT 563.684 494.976 Td /F1 9.8 Tf  [(. )] TJ ET
BT 26.250 483.072 Td /F1 9.8 Tf  [(Disagreement exists on the impact of combining other variables with mutational results in order to increase clinical sensitivity; )] TJ ET
BT 26.250 471.167 Td /F1 9.8 Tf  [(results vary by arrhythmia syndrome, genotype, and size of the study population)] TJ ET
0.267 0.267 0.267 rg
BT 371.449 472.674 Td /F4 8.7 Tf  [(10)] TJ ET
BT 381.086 472.674 Td /F4 8.7 Tf  [(27)] TJ ET
BT 390.723 472.674 Td /F4 8.7 Tf  [(60)] TJ ET
0.271 0.267 0.267 rg
BT 400.361 471.167 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 451.762 Td /F1 9.8 Tf  [(Mutational analysis of 27 )] TJ ET
BT 136.259 451.762 Td /F5 9.8 Tf  [(SCN5A)] TJ ET
BT 168.766 451.762 Td /F1 9.8 Tf  [( exons on cases from BrS databases at 9 international centers resulted in yields of 11-28%)] TJ ET
0.267 0.267 0.267 rg
BT 560.033 453.269 Td /F4 8.7 Tf  [(35)] TJ ET
BT 569.671 453.269 Td /F4 8.7 Tf  [(43)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 439.857 Td /F1 9.8 Tf  [(, lower than the 25-40% figure Transgenomic reports)] TJ ET
0.267 0.267 0.267 rg
BT 253.844 441.365 Td /F4 8.7 Tf  [(17)] TJ ET
BT 263.482 441.365 Td /F4 8.7 Tf  [(43)] TJ ET
BT 273.119 441.365 Td /F4 8.7 Tf  [(60)] TJ ET
0.271 0.267 0.267 rg
BT 282.756 439.857 Td /F1 9.8 Tf  [(. The literature suggests that for BrS about a quarter of the patients )] TJ ET
BT 26.250 427.953 Td /F1 9.8 Tf  [(or fewer carry an )] TJ ET
BT 102.105 427.953 Td /F5 9.8 Tf  [(SCN5A)] TJ ET
BT 134.612 427.953 Td /F1 9.8 Tf  [( mutation \(commercial assays also include other lower frequency mutations\))] TJ ET
0.267 0.267 0.267 rg
BT 462.426 429.460 Td /F4 8.7 Tf  [(1)] TJ ET
BT 467.245 429.460 Td /F4 8.7 Tf  [(2)] TJ ET
BT 472.063 429.460 Td /F4 8.7 Tf  [(25)] TJ ET
0.271 0.267 0.267 rg
BT 481.701 427.953 Td /F1 9.8 Tf  [(. The low clinical )] TJ ET
BT 26.250 416.048 Td /F1 9.8 Tf  [(sensitivity of genetic testing for Brugada syndrome, due to the low gene frequency for the most prevalent type of mutation )] TJ ET
BT 26.250 404.143 Td /F1 9.8 Tf  [(\(involving )] TJ ET
BT 70.135 404.143 Td /F5 9.8 Tf  [(SCN5A)] TJ ET
BT 102.641 404.143 Td /F1 9.8 Tf  [(\), incompleteness of known allelic variants, and the role of an organic substrate in many cases, limits its )] TJ ET
BT 26.250 392.238 Td /F1 9.8 Tf  [(diagnostic capability)] TJ ET
0.267 0.267 0.267 rg
BT 113.493 393.746 Td /F4 8.7 Tf  [(15)] TJ ET
BT 123.130 393.746 Td /F4 8.7 Tf  [(61)] TJ ET
BT 132.768 393.746 Td /F4 8.7 Tf  [(62)] TJ ET
0.271 0.267 0.267 rg
BT 142.405 392.238 Td /F1 9.8 Tf  [(. Genetic testing for BrS is more often used for confirmatory purposes)] TJ ET
0.267 0.267 0.267 rg
BT 442.071 393.746 Td /F4 8.7 Tf  [(1)] TJ ET
0.271 0.267 0.267 rg
BT 446.890 392.238 Td /F1 9.8 Tf  [(. Higher yields for the various )] TJ ET
BT 26.250 380.334 Td /F1 9.8 Tf  [(channelopathies accrue in families with at least one recorded case of sudden unexpected death, permitting detection of )] TJ ET
BT 26.250 368.429 Td /F1 9.8 Tf  [(potentially affected relatives)] TJ ET
0.267 0.267 0.267 rg
BT 146.555 369.936 Td /F4 8.7 Tf  [(24)] TJ ET
0.271 0.267 0.267 rg
BT 156.193 368.429 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 349.024 Td /F5 9.8 Tf  [(Clinical Utility:)] TJ ET
BT 26.250 329.619 Td /F1 9.8 Tf  [(Genetic analysis has been found useful in risk stratification of LQTS patients and detection of at-risk family members, though )] TJ ET
BT 26.250 317.715 Td /F1 9.8 Tf  [(current knowledge of CPVT genetic variants does not in itself does not yield prognostic information)] TJ ET
0.267 0.267 0.267 rg
BT 451.106 319.222 Td /F4 8.7 Tf  [(15)] TJ ET
BT 460.744 319.222 Td /F4 8.7 Tf  [(22)] TJ ET
BT 470.381 319.222 Td /F4 8.7 Tf  [(27)] TJ ET
BT 480.018 319.222 Td /F4 8.7 Tf  [(30)] TJ ET
BT 489.656 319.222 Td /F4 8.7 Tf  [(36)] TJ ET
BT 499.293 319.222 Td /F4 8.7 Tf  [(41)] TJ ET
BT 508.930 319.222 Td /F4 8.7 Tf  [(48)] TJ ET
0.271 0.267 0.267 rg
BT 518.568 317.715 Td /F1 9.8 Tf  [(. �Intragenic )] TJ ET
BT 26.250 305.810 Td /F1 9.8 Tf  [(risk stratification� based on mutation type and location, and cellular function, particularly for the LQT1 and 2 genotypes, has )] TJ ET
BT 26.250 293.905 Td /F1 9.8 Tf  [(been an increasing part of large scale studies but is not yet in widespread practice)] TJ ET
0.267 0.267 0.267 rg
BT 380.126 295.412 Td /F4 8.7 Tf  [(1)] TJ ET
BT 384.945 295.412 Td /F4 8.7 Tf  [(6)] TJ ET
BT 389.764 295.412 Td /F4 8.7 Tf  [(11)] TJ ET
BT 399.401 295.412 Td /F4 8.7 Tf  [(41)] TJ ET
BT 409.038 295.412 Td /F4 8.7 Tf  [(47)] TJ ET
BT 418.676 295.412 Td /F4 8.7 Tf  [(63)] TJ ET
0.271 0.267 0.267 rg
BT 428.313 293.905 Td /F1 9.8 Tf  [(. A meta-analysis of 30 Brugada )] TJ ET
BT 26.250 282.000 Td /F1 9.8 Tf  [(syndrome prospective studies by Gehi et al.)] TJ ET
0.267 0.267 0.267 rg
BT 215.371 283.508 Td /F4 8.7 Tf  [(64)] TJ ET
0.271 0.267 0.267 rg
BT 225.008 282.000 Td /F1 9.8 Tf  [( concluded family history of SCD and presence of an )] TJ ET
BT 454.777 282.000 Td /F5 9.8 Tf  [(SCN5A)] TJ ET
BT 487.283 282.000 Td /F1 9.8 Tf  [( mutation by )] TJ ET
BT 26.250 270.096 Td /F1 9.8 Tf  [(themselves are insufficient to predict risk for cardiac events in BrS. Instead, debates about risk stratification for patients with this )] TJ ET
BT 26.250 258.191 Td /F1 9.8 Tf  [(condition have taken place largely on the electrocardiographic front)] TJ ET
0.267 0.267 0.267 rg
BT 315.640 259.698 Td /F4 8.7 Tf  [(65)] TJ ET
0.271 0.267 0.267 rg
BT 325.277 258.191 Td /F1 9.8 Tf  [(. The presence of spontaneous ST-segment elevation, )] TJ ET
BT 26.250 246.286 Td /F1 9.8 Tf  [(particularly with a type-1 pattern, in conjunction with a history of syncope remains the strongest predictor of BrS risk)] TJ ET
0.267 0.267 0.267 rg
BT 523.695 247.793 Td /F4 8.7 Tf  [(2)] TJ ET
0.271 0.267 0.267 rg
BT 528.514 246.286 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 226.881 Td /F1 9.8 Tf  [(Mutational information can serve as an adjunct to clinical and phenotypic assessment of genotype in therapeutic decisions for )] TJ ET
BT 26.250 214.977 Td /F1 9.8 Tf  [(LQTS)] TJ ET
0.267 0.267 0.267 rg
BT 51.717 216.484 Td /F4 8.7 Tf  [(30)] TJ ET
BT 61.354 216.484 Td /F4 8.7 Tf  [(36)] TJ ET
BT 70.992 216.484 Td /F4 8.7 Tf  [(48)] TJ ET
0.271 0.267 0.267 rg
BT 80.629 214.977 Td /F1 9.8 Tf  [(, though this role is not without controversy)] TJ ET
0.267 0.267 0.267 rg
BT 265.421 216.484 Td /F4 8.7 Tf  [(10)] TJ ET
BT 275.058 216.484 Td /F4 8.7 Tf  [(12)] TJ ET
BT 284.695 216.484 Td /F4 8.7 Tf  [(16)] TJ ET
BT 294.333 216.484 Td /F4 8.7 Tf  [(41)] TJ ET
BT 303.970 216.484 Td /F4 8.7 Tf  [(66)] TJ ET
0.271 0.267 0.267 rg
BT 313.607 214.977 Td /F1 9.8 Tf  [(. Clear evidence exists for genotype-specific therapy in )] TJ ET
BT 26.250 203.072 Td /F1 9.8 Tf  [(management of the LQT1, 2, and 3 genotypes, but it is less substantiated for the other LQTS genotypes due to their rarity)] TJ ET
0.267 0.267 0.267 rg
BT 549.786 204.579 Td /F4 8.7 Tf  [(11)] TJ ET
BT 559.423 204.579 Td /F4 8.7 Tf  [(12)] TJ ET
BT 569.061 204.579 Td /F4 8.7 Tf  [(13)] TJ ET
BT 26.250 192.674 Td /F4 8.7 Tf  [(36)] TJ ET
BT 35.887 192.674 Td /F4 8.7 Tf  [(67)] TJ ET
BT 45.525 192.674 Td /F4 8.7 Tf  [(68)] TJ ET
0.271 0.267 0.267 rg
BT 55.162 191.167 Td /F1 9.8 Tf  [(. Disagreement exists on the use of intragenic, site-specific information to predict actual clinical phenotype or response to )] TJ ET
BT 26.250 179.262 Td /F1 9.8 Tf  [(therapy for the LQTS genotypes)] TJ ET
0.267 0.267 0.267 rg
BT 164.993 180.770 Td /F4 8.7 Tf  [(11)] TJ ET
BT 174.630 180.770 Td /F4 8.7 Tf  [(37)] TJ ET
0.271 0.267 0.267 rg
BT 184.267 179.262 Td /F1 9.8 Tf  [(. In analyzing retrospective data on 27 of 128 LQTS patients in the 3 to 13 year-old age )] TJ ET
BT 26.250 167.358 Td /F1 9.8 Tf  [(range who received either pacemakers or ICDs as therapy, investigators in a 3-area study \(Utah, British Columbia, and Arizona\) )] TJ ET
BT 26.250 155.453 Td /F1 9.8 Tf  [(found no association between device placement decisions and implementation of genetic testing. However, the authors also )] TJ ET
BT 26.250 143.548 Td /F1 9.8 Tf  [(noted that all patients with )] TJ ET
BT 141.690 143.548 Td /F5 9.8 Tf  [(SCN5A)] TJ ET
BT 174.197 143.548 Td /F1 9.8 Tf  [( \(LQT3\) mutations had therapeutic devices, though only 1 of 30 with a )] TJ ET
BT 477.685 143.548 Td /F5 9.8 Tf  [(KCNQ1)] TJ ET
BT 511.274 143.548 Td /F1 9.8 Tf  [( \(LQT1\) )] TJ ET
BT 26.250 131.643 Td /F1 9.8 Tf  [(mutation had one)] TJ ET
0.267 0.267 0.267 rg
BT 101.588 133.151 Td /F4 8.7 Tf  [(69)] TJ ET
0.271 0.267 0.267 rg
BT 111.226 131.643 Td /F1 9.8 Tf  [(. The use of genetic testing in therapeutic decision making for the other inherited arrhythmia syndromes is )] TJ ET
BT 26.250 119.739 Td /F1 9.8 Tf  [(not yet substantiated but appears promising)] TJ ET
0.267 0.267 0.267 rg
BT 215.390 121.246 Td /F4 8.7 Tf  [(16)] TJ ET
BT 225.028 121.246 Td /F4 8.7 Tf  [(30)] TJ ET
BT 234.665 121.246 Td /F4 8.7 Tf  [(48)] TJ ET
BT 244.302 121.246 Td /F4 8.7 Tf  [(70)] TJ ET
0.271 0.267 0.267 rg
BT 253.940 119.739 Td /F1 9.8 Tf  [(. ECG remains the principal tool for BrS diagnosis and therapeutic follow-up)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 109.341 Td /F4 8.7 Tf  [(2)] TJ ET
BT 31.069 109.341 Td /F4 8.7 Tf  [(16)] TJ ET
BT 40.706 109.341 Td /F4 8.7 Tf  [(25)] TJ ET
0.271 0.267 0.267 rg
BT 50.343 107.834 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 88.429 Td /F1 9.8 Tf  [(Several teams have evaluated step-wise or tiered strategies also including phenotypic assessment to increase the efficiency of )] TJ ET
BT 26.250 76.524 Td /F1 9.8 Tf  [(LQTS and CPVT genetic testing)] TJ ET
0.267 0.267 0.267 rg
BT 164.983 78.032 Td /F4 8.7 Tf  [(1)] TJ ET
BT 169.801 78.032 Td /F4 8.7 Tf  [(7)] TJ ET
BT 174.620 78.032 Td /F4 8.7 Tf  [(53)] TJ ET
BT 184.257 78.032 Td /F4 8.7 Tf  [(71)] TJ ET
BT 193.895 78.032 Td /F4 8.7 Tf  [(72)] TJ ET
0.271 0.267 0.267 rg
BT 203.532 76.524 Td /F1 9.8 Tf  [(. Targeted screening based on phenotypic information can lower the cost of more )] TJ ET
BT 26.250 64.620 Td /F1 9.8 Tf  [(comprehensive LQTS genetic testing by ~60% )] TJ ET
0.267 0.267 0.267 rg
BT 229.742 66.127 Td /F4 8.7 Tf  [(71)] TJ ET
0.271 0.267 0.267 rg
BT 239.380 64.620 Td /F1 9.8 Tf  [(. Phillips et al. found LQTS genetic testing more cost-effective than not testing )] TJ ET
BT 26.250 52.715 Td /F1 9.8 Tf  [(for symptomatic index cases at an estimated cost of $2,500 per year of life saved \($50,000 per year of life saved is often used )] TJ ET
BT 26.250 40.810 Td /F1 9.8 Tf  [(as a standard threshold\))] TJ ET
0.267 0.267 0.267 rg
BT 131.384 42.317 Td /F4 8.7 Tf  [(73)] TJ ET
BT 141.022 42.317 Td /F4 8.7 Tf  [(74)] TJ ET
0.271 0.267 0.267 rg
BT 150.659 40.810 Td /F1 9.8 Tf  [(. Bai et al., in looking at 546 patients referred to a large consortium of LQTS research laboratories, )] TJ ET
Q
q
15.000 26.524 577.500 750.476 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F1 9.8 Tf  [(duplication mutations \(generally on the scale of a whole exon or more\))] TJ ET
0.267 0.267 0.267 rg
BT 329.173 768.983 Td /F4 8.7 Tf  [(7)] TJ ET
BT 333.991 768.983 Td /F4 8.7 Tf  [(17)] TJ ET
0.271 0.267 0.267 rg
BT 343.629 767.476 Td /F1 9.8 Tf  [(. LQTS is in the upper range among cardiac )] TJ ET
BT 26.250 755.571 Td /F1 9.8 Tf  [(conditions in terms of number of affected genes \(13\) and allelic mutations \(>800\) while BrS lies in the midrange \(8 genes and )] TJ ET
BT 26.250 743.667 Td /F1 9.8 Tf  [(>400 allelic mutations\). By comparison, current compendia of arrhythmogenic right ventricular dysplasia/cardiomyopathy list 9 )] TJ ET
BT 26.250 731.762 Td /F1 9.8 Tf  [(affected genes and >400 allelic mutations, while Marfan syndrome has ~600 allelic mutations in the FBN1 fibrillin gene.)] TJ ET
BT 26.250 712.357 Td /F1 9.8 Tf  [(Authors have reported various mutational hotspots in the case of LQTS arising either independently or due to founder effects, )] TJ ET
BT 26.250 700.452 Td /F1 9.8 Tf  [(which because of their severity may aid risk stratification)] TJ ET
0.267 0.267 0.267 rg
BT 268.996 701.960 Td /F4 8.7 Tf  [(21)] TJ ET
0.271 0.267 0.267 rg
BT 278.633 700.452 Td /F1 9.8 Tf  [(. Interpretation of results for probands and family members is )] TJ ET
BT 26.250 688.548 Td /F1 9.8 Tf  [(complicated by variable penetrance in family members with the same genotype)] TJ ET
0.267 0.267 0.267 rg
BT 367.091 690.055 Td /F4 8.7 Tf  [(52)] TJ ET
0.271 0.267 0.267 rg
BT 376.728 688.548 Td /F1 9.8 Tf  [(, and the possibility of compound mutations, )] TJ ET
BT 26.250 676.643 Td /F1 9.8 Tf  [(observed in 4 to 10% of mutation positive individuals)] TJ ET
0.267 0.267 0.267 rg
BT 252.772 678.150 Td /F4 8.7 Tf  [(37)] TJ ET
BT 262.409 678.150 Td /F4 8.7 Tf  [(50)] TJ ET
BT 272.046 678.150 Td /F4 8.7 Tf  [(53)] TJ ET
BT 281.684 678.150 Td /F4 8.7 Tf  [(54)] TJ ET
0.271 0.267 0.267 rg
BT 291.321 676.643 Td /F1 9.8 Tf  [(. Estimated positive predictive values \(EPV � percent of mutations )] TJ ET
BT 26.250 664.738 Td /F1 9.8 Tf  [(found in definite cases that would cause the condition\) for LQTS genetic testing based on an assessment of > 1300 unrelated )] TJ ET
BT 26.250 652.833 Td /F1 9.8 Tf  [(index cases with Schwartz score >= 4 or QTc >= .48 s. are: 96% \(95% C.I., 94-98\) for )] TJ ET
BT 397.998 652.833 Td /F5 9.8 Tf  [(KCNQ1)] TJ ET
BT 431.587 652.833 Td /F1 9.8 Tf  [(; 93% \(89-95\) for )] TJ ET
BT 507.452 652.833 Td /F5 9.8 Tf  [(KCNH2)] TJ ET
BT 540.494 652.833 Td /F1 9.8 Tf  [(; and )] TJ ET
BT 26.250 640.929 Td /F1 9.8 Tf  [(63% \(40-77\) for )] TJ ET
BT 96.694 640.929 Td /F5 9.8 Tf  [(SCN5A)] TJ ET
0.267 0.267 0.267 rg
BT 129.200 642.436 Td /F4 8.7 Tf  [(55)] TJ ET
0.271 0.267 0.267 rg
BT 138.838 640.929 Td /F1 9.8 Tf  [(. Nonmissense mutations have an EPV > 99% regardless of location)] TJ ET
0.267 0.267 0.267 rg
BT 433.912 642.436 Td /F4 8.7 Tf  [(55)] TJ ET
0.271 0.267 0.267 rg
BT 443.549 640.929 Td /F1 9.8 Tf  [(. EPVs for missense mutations )] TJ ET
BT 26.250 629.024 Td /F1 9.8 Tf  [(range from 0% in the interdomain linker of )] TJ ET
BT 209.950 629.024 Td /F5 9.8 Tf  [(SCN5A)] TJ ET
BT 242.456 629.024 Td /F1 9.8 Tf  [( to 100% in the transmembrane/linker/pore regions of )] TJ ET
BT 474.935 629.024 Td /F5 9.8 Tf  [(KCNH2)] TJ ET
BT 507.978 629.024 Td /F1 9.8 Tf  [(. Similar figures )] TJ ET
BT 26.250 617.119 Td /F1 9.8 Tf  [(are lacking for the other channelopathies.)] TJ ET
BT 26.250 597.714 Td /F1 9.8 Tf  [(Several groups have investigated ECG genotyping \(to be distinguished from use in initial diagnosis\) through T-wave )] TJ ET
BT 26.250 585.810 Td /F1 9.8 Tf  [(morphology as a means of reducing the cost of LQTS mutational genotyping)] TJ ET
0.267 0.267 0.267 rg
BT 355.205 587.317 Td /F4 8.7 Tf  [(56)] TJ ET
BT 364.843 587.317 Td /F4 8.7 Tf  [(57)] TJ ET
BT 374.480 587.317 Td /F4 8.7 Tf  [(58)] TJ ET
0.271 0.267 0.267 rg
BT 384.117 585.810 Td /F1 9.8 Tf  [(. Sensitivity is highly dependent on the gene )] TJ ET
BT 26.250 573.905 Td /F1 9.8 Tf  [(being assessed, and varies between 92% \(LQT2\) and 47% \(LQT3\))] TJ ET
0.267 0.267 0.267 rg
BT 314.548 575.412 Td /F4 8.7 Tf  [(57)] TJ ET
BT 324.185 575.412 Td /F4 8.7 Tf  [(58)] TJ ET
0.271 0.267 0.267 rg
BT 333.822 573.905 Td /F1 9.8 Tf  [(. QTc interval alone lacks predictive value for genotyping)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 563.507 Td /F4 8.7 Tf  [(56)] TJ ET
BT 35.887 563.507 Td /F4 8.7 Tf  [(57)] TJ ET
0.271 0.267 0.267 rg
BT 45.525 562.000 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 542.595 Td /F1 9.8 Tf  [(For channelopathy genetic testing \(CGT\) of the other inherited arrhythmia syndromes, Transgenomic reports a clinical )] TJ ET
BT 26.250 530.691 Td /F1 9.8 Tf  [(sensitivity of 65-75% \(CPVT\), 25-40% \(BrS\), and 15-20% \(SQTS\))] TJ ET
0.267 0.267 0.267 rg
BT 309.088 532.198 Td /F4 8.7 Tf  [(17)] TJ ET
0.271 0.267 0.267 rg
BT 318.725 530.691 Td /F1 9.8 Tf  [(. GeneDx)] TJ ET
0.267 0.267 0.267 rg
BT 359.909 532.198 Td /F4 8.7 Tf  [(18)] TJ ET
0.271 0.267 0.267 rg
BT 369.546 530.691 Td /F1 9.8 Tf  [( and the Correlagen CardioGeneScan�)] TJ ET
0.267 0.267 0.267 rg
BT 540.396 532.198 Td /F4 8.7 Tf  [(59)] TJ ET
0.271 0.267 0.267 rg
BT 550.033 530.691 Td /F1 9.8 Tf  [( also )] TJ ET
BT 26.250 518.786 Td /F1 9.8 Tf  [(test for these conditions. The GeneDx and Correlagen test information / FAQ sheets provide rough estimates of clinical )] TJ ET
BT 26.250 506.881 Td /F1 9.8 Tf  [(sensitivity; figures from Correlagen are also reported with the assays. Some commercial laboratories only provide CPVT )] TJ ET
BT 26.250 494.976 Td /F1 9.8 Tf  [(screening of a limited number of select exons encompassing critical )] TJ ET
BT 320.486 494.976 Td /F5 9.8 Tf  [(RYR2)] TJ ET
BT 346.489 494.976 Td /F1 9.8 Tf  [( regions, which can contribute to false negatives)] TJ ET
0.267 0.267 0.267 rg
BT 554.047 496.484 Td /F4 8.7 Tf  [(30)] TJ ET
0.271 0.267 0.267 rg
BT 563.684 494.976 Td /F1 9.8 Tf  [(. )] TJ ET
BT 26.250 483.072 Td /F1 9.8 Tf  [(Disagreement exists on the impact of combining other variables with mutational results in order to increase clinical sensitivity; )] TJ ET
BT 26.250 471.167 Td /F1 9.8 Tf  [(results vary by arrhythmia syndrome, genotype, and size of the study population)] TJ ET
0.267 0.267 0.267 rg
BT 371.449 472.674 Td /F4 8.7 Tf  [(10)] TJ ET
BT 381.086 472.674 Td /F4 8.7 Tf  [(27)] TJ ET
BT 390.723 472.674 Td /F4 8.7 Tf  [(60)] TJ ET
0.271 0.267 0.267 rg
BT 400.361 471.167 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 451.762 Td /F1 9.8 Tf  [(Mutational analysis of 27 )] TJ ET
BT 136.259 451.762 Td /F5 9.8 Tf  [(SCN5A)] TJ ET
BT 168.766 451.762 Td /F1 9.8 Tf  [( exons on cases from BrS databases at 9 international centers resulted in yields of 11-28%)] TJ ET
0.267 0.267 0.267 rg
BT 560.033 453.269 Td /F4 8.7 Tf  [(35)] TJ ET
BT 569.671 453.269 Td /F4 8.7 Tf  [(43)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 439.857 Td /F1 9.8 Tf  [(, lower than the 25-40% figure Transgenomic reports)] TJ ET
0.267 0.267 0.267 rg
BT 253.844 441.365 Td /F4 8.7 Tf  [(17)] TJ ET
BT 263.482 441.365 Td /F4 8.7 Tf  [(43)] TJ ET
BT 273.119 441.365 Td /F4 8.7 Tf  [(60)] TJ ET
0.271 0.267 0.267 rg
BT 282.756 439.857 Td /F1 9.8 Tf  [(. The literature suggests that for BrS about a quarter of the patients )] TJ ET
BT 26.250 427.953 Td /F1 9.8 Tf  [(or fewer carry an )] TJ ET
BT 102.105 427.953 Td /F5 9.8 Tf  [(SCN5A)] TJ ET
BT 134.612 427.953 Td /F1 9.8 Tf  [( mutation \(commercial assays also include other lower frequency mutations\))] TJ ET
0.267 0.267 0.267 rg
BT 462.426 429.460 Td /F4 8.7 Tf  [(1)] TJ ET
BT 467.245 429.460 Td /F4 8.7 Tf  [(2)] TJ ET
BT 472.063 429.460 Td /F4 8.7 Tf  [(25)] TJ ET
0.271 0.267 0.267 rg
BT 481.701 427.953 Td /F1 9.8 Tf  [(. The low clinical )] TJ ET
BT 26.250 416.048 Td /F1 9.8 Tf  [(sensitivity of genetic testing for Brugada syndrome, due to the low gene frequency for the most prevalent type of mutation )] TJ ET
BT 26.250 404.143 Td /F1 9.8 Tf  [(\(involving )] TJ ET
BT 70.135 404.143 Td /F5 9.8 Tf  [(SCN5A)] TJ ET
BT 102.641 404.143 Td /F1 9.8 Tf  [(\), incompleteness of known allelic variants, and the role of an organic substrate in many cases, limits its )] TJ ET
BT 26.250 392.238 Td /F1 9.8 Tf  [(diagnostic capability)] TJ ET
0.267 0.267 0.267 rg
BT 113.493 393.746 Td /F4 8.7 Tf  [(15)] TJ ET
BT 123.130 393.746 Td /F4 8.7 Tf  [(61)] TJ ET
BT 132.768 393.746 Td /F4 8.7 Tf  [(62)] TJ ET
0.271 0.267 0.267 rg
BT 142.405 392.238 Td /F1 9.8 Tf  [(. Genetic testing for BrS is more often used for confirmatory purposes)] TJ ET
0.267 0.267 0.267 rg
BT 442.071 393.746 Td /F4 8.7 Tf  [(1)] TJ ET
0.271 0.267 0.267 rg
BT 446.890 392.238 Td /F1 9.8 Tf  [(. Higher yields for the various )] TJ ET
BT 26.250 380.334 Td /F1 9.8 Tf  [(channelopathies accrue in families with at least one recorded case of sudden unexpected death, permitting detection of )] TJ ET
BT 26.250 368.429 Td /F1 9.8 Tf  [(potentially affected relatives)] TJ ET
0.267 0.267 0.267 rg
BT 146.555 369.936 Td /F4 8.7 Tf  [(24)] TJ ET
0.271 0.267 0.267 rg
BT 156.193 368.429 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 349.024 Td /F5 9.8 Tf  [(Clinical Utility:)] TJ ET
BT 26.250 329.619 Td /F1 9.8 Tf  [(Genetic analysis has been found useful in risk stratification of LQTS patients and detection of at-risk family members, though )] TJ ET
BT 26.250 317.715 Td /F1 9.8 Tf  [(current knowledge of CPVT genetic variants does not in itself does not yield prognostic information)] TJ ET
0.267 0.267 0.267 rg
BT 451.106 319.222 Td /F4 8.7 Tf  [(15)] TJ ET
BT 460.744 319.222 Td /F4 8.7 Tf  [(22)] TJ ET
BT 470.381 319.222 Td /F4 8.7 Tf  [(27)] TJ ET
BT 480.018 319.222 Td /F4 8.7 Tf  [(30)] TJ ET
BT 489.656 319.222 Td /F4 8.7 Tf  [(36)] TJ ET
BT 499.293 319.222 Td /F4 8.7 Tf  [(41)] TJ ET
BT 508.930 319.222 Td /F4 8.7 Tf  [(48)] TJ ET
0.271 0.267 0.267 rg
BT 518.568 317.715 Td /F1 9.8 Tf  [(. �Intragenic )] TJ ET
BT 26.250 305.810 Td /F1 9.8 Tf  [(risk stratification� based on mutation type and location, and cellular function, particularly for the LQT1 and 2 genotypes, has )] TJ ET
BT 26.250 293.905 Td /F1 9.8 Tf  [(been an increasing part of large scale studies but is not yet in widespread practice)] TJ ET
0.267 0.267 0.267 rg
BT 380.126 295.412 Td /F4 8.7 Tf  [(1)] TJ ET
BT 384.945 295.412 Td /F4 8.7 Tf  [(6)] TJ ET
BT 389.764 295.412 Td /F4 8.7 Tf  [(11)] TJ ET
BT 399.401 295.412 Td /F4 8.7 Tf  [(41)] TJ ET
BT 409.038 295.412 Td /F4 8.7 Tf  [(47)] TJ ET
BT 418.676 295.412 Td /F4 8.7 Tf  [(63)] TJ ET
0.271 0.267 0.267 rg
BT 428.313 293.905 Td /F1 9.8 Tf  [(. A meta-analysis of 30 Brugada )] TJ ET
BT 26.250 282.000 Td /F1 9.8 Tf  [(syndrome prospective studies by Gehi et al.)] TJ ET
0.267 0.267 0.267 rg
BT 215.371 283.508 Td /F4 8.7 Tf  [(64)] TJ ET
0.271 0.267 0.267 rg
BT 225.008 282.000 Td /F1 9.8 Tf  [( concluded family history of SCD and presence of an )] TJ ET
BT 454.777 282.000 Td /F5 9.8 Tf  [(SCN5A)] TJ ET
BT 487.283 282.000 Td /F1 9.8 Tf  [( mutation by )] TJ ET
BT 26.250 270.096 Td /F1 9.8 Tf  [(themselves are insufficient to predict risk for cardiac events in BrS. Instead, debates about risk stratification for patients with this )] TJ ET
BT 26.250 258.191 Td /F1 9.8 Tf  [(condition have taken place largely on the electrocardiographic front)] TJ ET
0.267 0.267 0.267 rg
BT 315.640 259.698 Td /F4 8.7 Tf  [(65)] TJ ET
0.271 0.267 0.267 rg
BT 325.277 258.191 Td /F1 9.8 Tf  [(. The presence of spontaneous ST-segment elevation, )] TJ ET
BT 26.250 246.286 Td /F1 9.8 Tf  [(particularly with a type-1 pattern, in conjunction with a history of syncope remains the strongest predictor of BrS risk)] TJ ET
0.267 0.267 0.267 rg
BT 523.695 247.793 Td /F4 8.7 Tf  [(2)] TJ ET
0.271 0.267 0.267 rg
BT 528.514 246.286 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 226.881 Td /F1 9.8 Tf  [(Mutational information can serve as an adjunct to clinical and phenotypic assessment of genotype in therapeutic decisions for )] TJ ET
BT 26.250 214.977 Td /F1 9.8 Tf  [(LQTS)] TJ ET
0.267 0.267 0.267 rg
BT 51.717 216.484 Td /F4 8.7 Tf  [(30)] TJ ET
BT 61.354 216.484 Td /F4 8.7 Tf  [(36)] TJ ET
BT 70.992 216.484 Td /F4 8.7 Tf  [(48)] TJ ET
0.271 0.267 0.267 rg
BT 80.629 214.977 Td /F1 9.8 Tf  [(, though this role is not without controversy)] TJ ET
0.267 0.267 0.267 rg
BT 265.421 216.484 Td /F4 8.7 Tf  [(10)] TJ ET
BT 275.058 216.484 Td /F4 8.7 Tf  [(12)] TJ ET
BT 284.695 216.484 Td /F4 8.7 Tf  [(16)] TJ ET
BT 294.333 216.484 Td /F4 8.7 Tf  [(41)] TJ ET
BT 303.970 216.484 Td /F4 8.7 Tf  [(66)] TJ ET
0.271 0.267 0.267 rg
BT 313.607 214.977 Td /F1 9.8 Tf  [(. Clear evidence exists for genotype-specific therapy in )] TJ ET
BT 26.250 203.072 Td /F1 9.8 Tf  [(management of the LQT1, 2, and 3 genotypes, but it is less substantiated for the other LQTS genotypes due to their rarity)] TJ ET
0.267 0.267 0.267 rg
BT 549.786 204.579 Td /F4 8.7 Tf  [(11)] TJ ET
BT 559.423 204.579 Td /F4 8.7 Tf  [(12)] TJ ET
BT 569.061 204.579 Td /F4 8.7 Tf  [(13)] TJ ET
BT 26.250 192.674 Td /F4 8.7 Tf  [(36)] TJ ET
BT 35.887 192.674 Td /F4 8.7 Tf  [(67)] TJ ET
BT 45.525 192.674 Td /F4 8.7 Tf  [(68)] TJ ET
0.271 0.267 0.267 rg
BT 55.162 191.167 Td /F1 9.8 Tf  [(. Disagreement exists on the use of intragenic, site-specific information to predict actual clinical phenotype or response to )] TJ ET
BT 26.250 179.262 Td /F1 9.8 Tf  [(therapy for the LQTS genotypes)] TJ ET
0.267 0.267 0.267 rg
BT 164.993 180.770 Td /F4 8.7 Tf  [(11)] TJ ET
BT 174.630 180.770 Td /F4 8.7 Tf  [(37)] TJ ET
0.271 0.267 0.267 rg
BT 184.267 179.262 Td /F1 9.8 Tf  [(. In analyzing retrospective data on 27 of 128 LQTS patients in the 3 to 13 year-old age )] TJ ET
BT 26.250 167.358 Td /F1 9.8 Tf  [(range who received either pacemakers or ICDs as therapy, investigators in a 3-area study \(Utah, British Columbia, and Arizona\) )] TJ ET
BT 26.250 155.453 Td /F1 9.8 Tf  [(found no association between device placement decisions and implementation of genetic testing. However, the authors also )] TJ ET
BT 26.250 143.548 Td /F1 9.8 Tf  [(noted that all patients with )] TJ ET
BT 141.690 143.548 Td /F5 9.8 Tf  [(SCN5A)] TJ ET
BT 174.197 143.548 Td /F1 9.8 Tf  [( \(LQT3\) mutations had therapeutic devices, though only 1 of 30 with a )] TJ ET
BT 477.685 143.548 Td /F5 9.8 Tf  [(KCNQ1)] TJ ET
BT 511.274 143.548 Td /F1 9.8 Tf  [( \(LQT1\) )] TJ ET
BT 26.250 131.643 Td /F1 9.8 Tf  [(mutation had one)] TJ ET
0.267 0.267 0.267 rg
BT 101.588 133.151 Td /F4 8.7 Tf  [(69)] TJ ET
0.271 0.267 0.267 rg
BT 111.226 131.643 Td /F1 9.8 Tf  [(. The use of genetic testing in therapeutic decision making for the other inherited arrhythmia syndromes is )] TJ ET
BT 26.250 119.739 Td /F1 9.8 Tf  [(not yet substantiated but appears promising)] TJ ET
0.267 0.267 0.267 rg
BT 215.390 121.246 Td /F4 8.7 Tf  [(16)] TJ ET
BT 225.028 121.246 Td /F4 8.7 Tf  [(30)] TJ ET
BT 234.665 121.246 Td /F4 8.7 Tf  [(48)] TJ ET
BT 244.302 121.246 Td /F4 8.7 Tf  [(70)] TJ ET
0.271 0.267 0.267 rg
BT 253.940 119.739 Td /F1 9.8 Tf  [(. ECG remains the principal tool for BrS diagnosis and therapeutic follow-up)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 109.341 Td /F4 8.7 Tf  [(2)] TJ ET
BT 31.069 109.341 Td /F4 8.7 Tf  [(16)] TJ ET
BT 40.706 109.341 Td /F4 8.7 Tf  [(25)] TJ ET
0.271 0.267 0.267 rg
BT 50.343 107.834 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 88.429 Td /F1 9.8 Tf  [(Several teams have evaluated step-wise or tiered strategies also including phenotypic assessment to increase the efficiency of )] TJ ET
BT 26.250 76.524 Td /F1 9.8 Tf  [(LQTS and CPVT genetic testing)] TJ ET
0.267 0.267 0.267 rg
BT 164.983 78.032 Td /F4 8.7 Tf  [(1)] TJ ET
BT 169.801 78.032 Td /F4 8.7 Tf  [(7)] TJ ET
BT 174.620 78.032 Td /F4 8.7 Tf  [(53)] TJ ET
BT 184.257 78.032 Td /F4 8.7 Tf  [(71)] TJ ET
BT 193.895 78.032 Td /F4 8.7 Tf  [(72)] TJ ET
0.271 0.267 0.267 rg
BT 203.532 76.524 Td /F1 9.8 Tf  [(. Targeted screening based on phenotypic information can lower the cost of more )] TJ ET
BT 26.250 64.620 Td /F1 9.8 Tf  [(comprehensive LQTS genetic testing by ~60% )] TJ ET
0.267 0.267 0.267 rg
BT 229.742 66.127 Td /F4 8.7 Tf  [(71)] TJ ET
0.271 0.267 0.267 rg
BT 239.380 64.620 Td /F1 9.8 Tf  [(. Phillips et al. found LQTS genetic testing more cost-effective than not testing )] TJ ET
BT 26.250 52.715 Td /F1 9.8 Tf  [(for symptomatic index cases at an estimated cost of $2,500 per year of life saved \($50,000 per year of life saved is often used )] TJ ET
BT 26.250 40.810 Td /F1 9.8 Tf  [(as a standard threshold\))] TJ ET
0.267 0.267 0.267 rg
BT 131.384 42.317 Td /F4 8.7 Tf  [(73)] TJ ET
BT 141.022 42.317 Td /F4 8.7 Tf  [(74)] TJ ET
0.271 0.267 0.267 rg
BT 150.659 40.810 Td /F1 9.8 Tf  [(. Bai et al., in looking at 546 patients referred to a large consortium of LQTS research laboratories, )] TJ ET
Q
q
0.000 0.000 0.000 rg
BT 291.710 19.825 Td /F1 11.0 Tf  [(4)] TJ ET
BT 25.000 19.825 Td /F1 11.0 Tf  [(PLOS Currents Evidence on Genomic Tests)] TJ ET

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15.000 21.209 577.500 755.791 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F1 9.8 Tf  [(found the highest yield \(64%\) and lowest cost \($8,418 per positive genotyping\) for patients with ECG-confirmed LQTS, but )] TJ ET
BT 26.250 755.571 Td /F1 9.8 Tf  [(diminishing yields and increasing costs for patients with borderline QTc intervals and those with normal intervals but a positive )] TJ ET
BT 26.250 743.667 Td /F1 9.8 Tf  [(family history for SCD)] TJ ET
0.267 0.267 0.267 rg
BT 120.513 745.174 Td /F4 8.7 Tf  [(60)] TJ ET
0.271 0.267 0.267 rg
BT 130.150 743.667 Td /F1 9.8 Tf  [(. They recommended genetic testing be prioritized to those with a �conclusive diagnosis� of LQTS. )] TJ ET
BT 26.250 731.762 Td /F1 9.8 Tf  [(Genotyping of individuals with a conclusive diagnosis of CPVT, and of patients with type 1 BrS ECG with atrioventricular block )] TJ ET
BT 26.250 719.857 Td /F1 9.8 Tf  [(was also found to be cost-effective. Apart from this report, the host of cost-effectiveness analyses for Brugada syndrome deal )] TJ ET
BT 26.250 707.952 Td /F1 9.8 Tf  [(with the issue of implantation of ICDs.)] TJ ET
BT 26.250 688.548 Td /F1 9.8 Tf  [(Perez et al. used a Markov model to assess the cost-effectiveness of different strategies for testing then treating an )] TJ ET
BT 26.250 676.643 Td /F1 9.8 Tf  [(asymptomatic 10 year-old first degree relative of a patient with clinically evident LQTS)] TJ ET
0.267 0.267 0.267 rg
BT 395.804 678.150 Td /F4 8.7 Tf  [(75)] TJ ET
0.271 0.267 0.267 rg
BT 405.442 676.643 Td /F1 9.8 Tf  [(. They concluded that genetic testing is )] TJ ET
BT 26.250 664.738 Td /F1 9.8 Tf  [(moderately expensive, at $67,400 per quality adjusted life year saved, but improves with higher clinical suspicion of the )] TJ ET
BT 26.250 652.833 Td /F1 9.8 Tf  [(proband, number of relatives tested, and stronger family history of sudden death.)] TJ ET
BT 26.250 633.429 Td /F1 9.8 Tf  [(CGT is covered to different extents by insurance providers, ranging from denial to 100% coverage, with most covering at least )] TJ ET
BT 26.250 621.524 Td /F1 9.8 Tf  [(50 to 75% of the cost)] TJ ET
0.267 0.267 0.267 rg
BT 117.851 623.031 Td /F4 8.7 Tf  [(22)] TJ ET
0.271 0.267 0.267 rg
BT 127.489 621.524 Td /F1 9.8 Tf  [(. Some health plan policies explicitly limit genetic test reimbursement to LQTS while excluding the other )] TJ ET
BT 26.250 609.619 Td /F1 9.8 Tf  [(channelopathies)] TJ ET
0.267 0.267 0.267 rg
BT 97.249 611.126 Td /F4 8.7 Tf  [(76)] TJ ET
0.271 0.267 0.267 rg
BT 106.887 609.619 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 590.214 Td /F5 9.8 Tf  [(Public Health Ethical, Legal, and Social \(PHELSI\) Considerations:)] TJ ET
BT 26.250 570.810 Td /F1 9.8 Tf  [(Genetic testing for cardiac channelopathies is laden with ethical issues, including the search for a balance between individual )] TJ ET
BT 26.250 558.905 Td /F1 9.8 Tf  [(privacy vs. alerting at-risk family members, as well as psychosocial issues inherent in informing individuals of their risk)] TJ ET
0.267 0.267 0.267 rg
BT 534.469 560.412 Td /F4 8.7 Tf  [(1)] TJ ET
BT 539.287 560.412 Td /F4 8.7 Tf  [(77)] TJ ET
BT 548.925 560.412 Td /F4 8.7 Tf  [(78)] TJ ET
0.271 0.267 0.267 rg
BT 558.562 558.905 Td /F1 9.8 Tf  [(. A )] TJ ET
BT 26.250 547.000 Td /F1 9.8 Tf  [(review by Wren provides general recommendations for genetic testing of children in families with a history of SCD, and offers )] TJ ET
BT 26.250 535.095 Td /F1 9.8 Tf  [(ethical considerations in childhood genetic testing for Brugada syndrome)] TJ ET
0.267 0.267 0.267 rg
BT 339.478 536.603 Td /F4 8.7 Tf  [(79)] TJ ET
0.271 0.267 0.267 rg
BT 349.116 535.095 Td /F1 9.8 Tf  [(. Use of pacemakers and ICDs in children, while )] TJ ET
BT 26.250 523.191 Td /F1 9.8 Tf  [(often done under situations of medical necessity, can involve trade-offs between benefit and adverse effects)] TJ ET
0.267 0.267 0.267 rg
BT 491.783 524.698 Td /F4 8.7 Tf  [(45)] TJ ET
BT 501.421 524.698 Td /F4 8.7 Tf  [(69)] TJ ET
BT 511.058 524.698 Td /F4 8.7 Tf  [(80)] TJ ET
0.271 0.267 0.267 rg
BT 520.695 523.191 Td /F1 9.8 Tf  [(. Screening )] TJ ET
BT 26.250 511.286 Td /F1 9.8 Tf  [(for LQTS mutations in particular racial-ethnic groups deserves further ethical analysis)] TJ ET
0.267 0.267 0.267 rg
BT 393.630 512.793 Td /F4 8.7 Tf  [(21)] TJ ET
0.271 0.267 0.267 rg
BT 403.267 511.286 Td /F1 9.8 Tf  [(. Personalization of drug treatment )] TJ ET
BT 26.250 499.381 Td /F1 9.8 Tf  [(through determination of individually specific genotype remains a hoped-for future direction in the field)] TJ ET
0.267 0.267 0.267 rg
BT 464.659 500.888 Td /F4 8.7 Tf  [(1)] TJ ET
BT 469.477 500.888 Td /F4 8.7 Tf  [(75)] TJ ET
0.271 0.267 0.267 rg
BT 479.115 499.381 Td /F1 9.8 Tf  [(. Risk assessment for )] TJ ET
BT 26.250 487.476 Td /F1 9.8 Tf  [(inherited heart arrhythmias is also becoming a part of direct-to-consumer genetic testing, an area subject to increasing attention )] TJ ET
BT 26.250 475.572 Td /F1 9.8 Tf  [(by policy makers.)] TJ ET
BT 26.250 438.969 Td /F4 12.0 Tf  [(Links)] TJ ET
BT 26.250 419.015 Td /F1 9.8 Tf  [(The commercial and university-based laboratories cited above are approved under the Clinical Laboratory Improvement )] TJ ET
BT 26.250 407.110 Td /F1 9.8 Tf  [(Amendments \(CLIA\). Several, but not all, are accredited by the College of American Pathologists \(CAP\). These assays are )] TJ ET
BT 26.250 395.205 Td /F1 9.8 Tf  [(developed and validated in-house, thus do not require FDA approval.)] TJ ET
BT 26.250 375.801 Td /F1 9.8 Tf  [(Relevant web sites:)] TJ ET
0.271 0.267 0.267 RG
40.337 359.364 m 
40.337 359.810 40.154 360.254 39.838 360.570 c
39.522 360.886 39.078 361.070 38.631 361.070 c
38.185 361.070 37.741 360.886 37.425 360.570 c
37.109 360.254 36.925 359.810 36.925 359.364 c
36.925 358.917 37.109 358.473 37.425 358.157 c
37.741 357.841 38.185 357.657 38.631 357.657 c
39.078 357.657 39.522 357.841 39.838 358.157 c
40.154 358.473 40.337 358.917 40.337 359.364 c f
BT 45.750 356.396 Td /F1 9.8 Tf  [(IRCCS Fondazione Salvatore Maugeri Molecular Cardiology Laboratories. Gene Connection for the Heart Inherited )] TJ ET
BT 45.750 344.491 Td /F1 9.8 Tf  [(Arrhythmias Database. )] TJ ET
0.267 0.267 0.267 rg
BT 147.618 344.491 Td /F1 9.8 Tf  [(www.fsm.it/cardmoc)] TJ ET
0.271 0.267 0.267 rg
BT 234.832 344.491 Td /F1 9.8 Tf  [(. Up-to-date compendium of inherited arrhythmia syndrome \(cardiac ion )] TJ ET
BT 45.750 332.586 Td /F1 9.8 Tf  [(channelopathy, arrhythmogenic right ventricular cardiomyopathy, and others\) mutations and polymorphisms, and condition )] TJ ET
BT 45.750 320.682 Td /F1 9.8 Tf  [(synopses.)] TJ ET
40.337 307.995 m 
40.337 308.441 40.154 308.885 39.838 309.201 c
39.522 309.517 39.078 309.701 38.631 309.701 c
38.185 309.701 37.741 309.517 37.425 309.201 c
37.109 308.885 36.925 308.441 36.925 307.995 c
36.925 307.548 37.109 307.104 37.425 306.788 c
37.741 306.472 38.185 306.288 38.631 306.288 c
39.078 306.288 39.522 306.472 39.838 306.788 c
40.154 307.104 40.337 307.548 40.337 307.995 c f
BT 45.750 305.027 Td /F1 9.8 Tf  [(Heart Rhythm Society.)] TJ ET
0.267 0.267 0.267 rg
BT 143.279 305.027 Td /F1 9.8 Tf  [( www.hrsonline.org)] TJ ET
0.271 0.267 0.267 rg
BT 226.174 305.027 Td /F1 9.8 Tf  [(. International society concerned with education and advocacy for cardiac )] TJ ET
BT 45.750 293.122 Td /F1 9.8 Tf  [(arrhythmia professionals and patients. Web site describes and provides access to professional educational programs, )] TJ ET
BT 45.750 281.217 Td /F1 9.8 Tf  [(clinical guidelines and consensus statements relating to diagnosis and management, and relevant legislation.)] TJ ET
40.337 268.530 m 
40.337 268.977 40.154 269.421 39.838 269.737 c
39.522 270.053 39.078 270.237 38.631 270.237 c
38.185 270.237 37.741 270.053 37.425 269.737 c
37.109 269.421 36.925 268.977 36.925 268.530 c
36.925 268.084 37.109 267.640 37.425 267.324 c
37.741 267.008 38.185 266.824 38.631 266.824 c
39.078 266.824 39.522 267.008 39.838 267.324 c
40.154 267.640 40.337 268.084 40.337 268.530 c f
BT 45.750 265.563 Td /F1 9.8 Tf  [(Cardiac Arrhythmias Research and Education \(CARE\) Foundation. )] TJ ET
0.267 0.267 0.267 rg
BT 336.729 265.563 Td /F1 9.8 Tf  [(www.longqt.com)] TJ ET
0.271 0.267 0.267 rg
BT 408.245 265.563 Td /F1 9.8 Tf  [(. Advocacy and awareness-raising )] TJ ET
BT 45.750 253.658 Td /F1 9.8 Tf  [(organization aimed at preventing sudden cardiac death due to acquired and heritable heart rhythm disorders. Web site )] TJ ET
BT 45.750 241.753 Td /F1 9.8 Tf  [(reports professional educational resources, and details emerging advocacy issues, support groups, and genetic testing )] TJ ET
BT 45.750 229.848 Td /F1 9.8 Tf  [(laboratories.)] TJ ET
40.337 217.161 m 
40.337 217.608 40.154 218.052 39.838 218.368 c
39.522 218.684 39.078 218.868 38.631 218.868 c
38.185 218.868 37.741 218.684 37.425 218.368 c
37.109 218.052 36.925 217.608 36.925 217.161 c
36.925 216.715 37.109 216.271 37.425 215.955 c
37.741 215.639 38.185 215.455 38.631 215.455 c
39.078 215.455 39.522 215.639 39.838 215.955 c
40.154 216.271 40.337 216.715 40.337 217.161 c f
BT 45.750 214.194 Td /F1 9.8 Tf  [(Sudden Arrhythmia Death Syndromes Foundation. )] TJ ET
0.267 0.267 0.267 rg
BT 266.851 214.194 Td /F1 9.8 Tf  [(www.sads.org)] TJ ET
0.271 0.267 0.267 rg
BT 328.071 214.194 Td /F1 9.8 Tf  [(. Aimed at preventing sudden and unexpected cardiac )] TJ ET
BT 45.750 202.289 Td /F1 9.8 Tf  [(death in children and young adults, the Foundation�s web site describes public awareness-raising activities, advocacy )] TJ ET
BT 45.750 190.384 Td /F1 9.8 Tf  [(initiatives impacting patients and professionals, and patient and family support services.)] TJ ET
40.337 177.697 m 
40.337 178.144 40.154 178.588 39.838 178.904 c
39.522 179.219 39.078 179.403 38.631 179.403 c
38.185 179.403 37.741 179.219 37.425 178.904 c
37.109 178.588 36.925 178.144 36.925 177.697 c
36.925 177.250 37.109 176.806 37.425 176.490 c
37.741 176.175 38.185 175.991 38.631 175.991 c
39.078 175.991 39.522 176.175 39.838 176.490 c
40.154 176.806 40.337 177.250 40.337 177.697 c f
BT 45.750 174.729 Td /F1 9.8 Tf  [(Drugs that Prolong the QT Interval and/or Induce Torsades de Pointes Ventricular Arrhythmia.)] TJ ET
0.267 0.267 0.267 rg
BT 450.550 174.729 Td /F1 9.8 Tf  [( www.qtdrugs.org)] TJ ET
0.271 0.267 0.267 rg
BT 526.406 174.729 Td /F1 9.8 Tf  [(. Web site )] TJ ET
BT 45.750 162.825 Td /F1 9.8 Tf  [(provides a comprehensive list of arrhythmogenic drugs to be avoided by LQTS patients, lists drugs by risk group, provides )] TJ ET
BT 45.750 150.920 Td /F1 9.8 Tf  [(consumer education tools, and describes the drug-induced arrhythmias case registry.)] TJ ET
40.337 138.233 m 
40.337 138.679 40.154 139.123 39.838 139.439 c
39.522 139.755 39.078 139.939 38.631 139.939 c
38.185 139.939 37.741 139.755 37.425 139.439 c
37.109 139.123 36.925 138.679 36.925 138.233 c
36.925 137.786 37.109 137.342 37.425 137.026 c
37.741 136.710 38.185 136.527 38.631 136.527 c
39.078 136.527 39.522 136.710 39.838 137.026 c
40.154 137.342 40.337 137.786 40.337 138.233 c f
BT 45.750 135.265 Td /F1 9.8 Tf  [(Raymond Brugada Senior Foundation, )] TJ ET
0.267 0.267 0.267 rg
BT 214.834 135.265 Td /F1 9.8 Tf  [(www.brugada.org)] TJ ET
0.271 0.267 0.267 rg
BT 291.236 135.265 Td /F1 9.8 Tf  [(. Foundation web site provides a full description of Brugada )] TJ ET
BT 45.750 123.360 Td /F1 9.8 Tf  [(syndrome, cites relevant literature and professional policies, and offers avenues for partnering in research and joining a )] TJ ET
BT 45.750 111.456 Td /F1 9.8 Tf  [(support group.)] TJ ET
40.337 98.769 m 
40.337 99.215 40.154 99.659 39.838 99.975 c
39.522 100.291 39.078 100.475 38.631 100.475 c
38.185 100.475 37.741 100.291 37.425 99.975 c
37.109 99.659 36.925 99.215 36.925 98.769 c
36.925 98.322 37.109 97.878 37.425 97.562 c
37.741 97.246 38.185 97.062 38.631 97.062 c
39.078 97.062 39.522 97.246 39.838 97.562 c
40.154 97.878 40.337 98.322 40.337 98.769 c f
BT 45.750 95.801 Td /F1 9.8 Tf  [(BrugadaDrugs.org. )] TJ ET
0.267 0.267 0.267 rg
BT 130.829 95.801 Td /F1 9.8 Tf  [(www.brugadadrugs.org)] TJ ET
0.271 0.267 0.267 rg
BT 231.614 95.801 Td /F1 9.8 Tf  [(. Web site provides a comprehensive list of arrhythmogenic drugs to be avoided )] TJ ET
BT 45.750 83.896 Td /F1 9.8 Tf  [(by Brudaga syndrome patients, lists drugs by risk group, cites drugs diagnostic for Brs, and offers a patient letter listing )] TJ ET
BT 45.750 71.991 Td /F1 9.8 Tf  [(drugs to be avoided.)] TJ ET
Q
q
15.000 21.209 577.500 755.791 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F1 9.8 Tf  [(found the highest yield \(64%\) and lowest cost \($8,418 per positive genotyping\) for patients with ECG-confirmed LQTS, but )] TJ ET
BT 26.250 755.571 Td /F1 9.8 Tf  [(diminishing yields and increasing costs for patients with borderline QTc intervals and those with normal intervals but a positive )] TJ ET
BT 26.250 743.667 Td /F1 9.8 Tf  [(family history for SCD)] TJ ET
0.267 0.267 0.267 rg
BT 120.513 745.174 Td /F4 8.7 Tf  [(60)] TJ ET
0.271 0.267 0.267 rg
BT 130.150 743.667 Td /F1 9.8 Tf  [(. They recommended genetic testing be prioritized to those with a �conclusive diagnosis� of LQTS. )] TJ ET
BT 26.250 731.762 Td /F1 9.8 Tf  [(Genotyping of individuals with a conclusive diagnosis of CPVT, and of patients with type 1 BrS ECG with atrioventricular block )] TJ ET
BT 26.250 719.857 Td /F1 9.8 Tf  [(was also found to be cost-effective. Apart from this report, the host of cost-effectiveness analyses for Brugada syndrome deal )] TJ ET
BT 26.250 707.952 Td /F1 9.8 Tf  [(with the issue of implantation of ICDs.)] TJ ET
BT 26.250 688.548 Td /F1 9.8 Tf  [(Perez et al. used a Markov model to assess the cost-effectiveness of different strategies for testing then treating an )] TJ ET
BT 26.250 676.643 Td /F1 9.8 Tf  [(asymptomatic 10 year-old first degree relative of a patient with clinically evident LQTS)] TJ ET
0.267 0.267 0.267 rg
BT 395.804 678.150 Td /F4 8.7 Tf  [(75)] TJ ET
0.271 0.267 0.267 rg
BT 405.442 676.643 Td /F1 9.8 Tf  [(. They concluded that genetic testing is )] TJ ET
BT 26.250 664.738 Td /F1 9.8 Tf  [(moderately expensive, at $67,400 per quality adjusted life year saved, but improves with higher clinical suspicion of the )] TJ ET
BT 26.250 652.833 Td /F1 9.8 Tf  [(proband, number of relatives tested, and stronger family history of sudden death.)] TJ ET
BT 26.250 633.429 Td /F1 9.8 Tf  [(CGT is covered to different extents by insurance providers, ranging from denial to 100% coverage, with most covering at least )] TJ ET
BT 26.250 621.524 Td /F1 9.8 Tf  [(50 to 75% of the cost)] TJ ET
0.267 0.267 0.267 rg
BT 117.851 623.031 Td /F4 8.7 Tf  [(22)] TJ ET
0.271 0.267 0.267 rg
BT 127.489 621.524 Td /F1 9.8 Tf  [(. Some health plan policies explicitly limit genetic test reimbursement to LQTS while excluding the other )] TJ ET
BT 26.250 609.619 Td /F1 9.8 Tf  [(channelopathies)] TJ ET
0.267 0.267 0.267 rg
BT 97.249 611.126 Td /F4 8.7 Tf  [(76)] TJ ET
0.271 0.267 0.267 rg
BT 106.887 609.619 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 590.214 Td /F5 9.8 Tf  [(Public Health Ethical, Legal, and Social \(PHELSI\) Considerations:)] TJ ET
BT 26.250 570.810 Td /F1 9.8 Tf  [(Genetic testing for cardiac channelopathies is laden with ethical issues, including the search for a balance between individual )] TJ ET
BT 26.250 558.905 Td /F1 9.8 Tf  [(privacy vs. alerting at-risk family members, as well as psychosocial issues inherent in informing individuals of their risk)] TJ ET
0.267 0.267 0.267 rg
BT 534.469 560.412 Td /F4 8.7 Tf  [(1)] TJ ET
BT 539.287 560.412 Td /F4 8.7 Tf  [(77)] TJ ET
BT 548.925 560.412 Td /F4 8.7 Tf  [(78)] TJ ET
0.271 0.267 0.267 rg
BT 558.562 558.905 Td /F1 9.8 Tf  [(. A )] TJ ET
BT 26.250 547.000 Td /F1 9.8 Tf  [(review by Wren provides general recommendations for genetic testing of children in families with a history of SCD, and offers )] TJ ET
BT 26.250 535.095 Td /F1 9.8 Tf  [(ethical considerations in childhood genetic testing for Brugada syndrome)] TJ ET
0.267 0.267 0.267 rg
BT 339.478 536.603 Td /F4 8.7 Tf  [(79)] TJ ET
0.271 0.267 0.267 rg
BT 349.116 535.095 Td /F1 9.8 Tf  [(. Use of pacemakers and ICDs in children, while )] TJ ET
BT 26.250 523.191 Td /F1 9.8 Tf  [(often done under situations of medical necessity, can involve trade-offs between benefit and adverse effects)] TJ ET
0.267 0.267 0.267 rg
BT 491.783 524.698 Td /F4 8.7 Tf  [(45)] TJ ET
BT 501.421 524.698 Td /F4 8.7 Tf  [(69)] TJ ET
BT 511.058 524.698 Td /F4 8.7 Tf  [(80)] TJ ET
0.271 0.267 0.267 rg
BT 520.695 523.191 Td /F1 9.8 Tf  [(. Screening )] TJ ET
BT 26.250 511.286 Td /F1 9.8 Tf  [(for LQTS mutations in particular racial-ethnic groups deserves further ethical analysis)] TJ ET
0.267 0.267 0.267 rg
BT 393.630 512.793 Td /F4 8.7 Tf  [(21)] TJ ET
0.271 0.267 0.267 rg
BT 403.267 511.286 Td /F1 9.8 Tf  [(. Personalization of drug treatment )] TJ ET
BT 26.250 499.381 Td /F1 9.8 Tf  [(through determination of individually specific genotype remains a hoped-for future direction in the field)] TJ ET
0.267 0.267 0.267 rg
BT 464.659 500.888 Td /F4 8.7 Tf  [(1)] TJ ET
BT 469.477 500.888 Td /F4 8.7 Tf  [(75)] TJ ET
0.271 0.267 0.267 rg
BT 479.115 499.381 Td /F1 9.8 Tf  [(. Risk assessment for )] TJ ET
BT 26.250 487.476 Td /F1 9.8 Tf  [(inherited heart arrhythmias is also becoming a part of direct-to-consumer genetic testing, an area subject to increasing attention )] TJ ET
BT 26.250 475.572 Td /F1 9.8 Tf  [(by policy makers.)] TJ ET
BT 26.250 438.969 Td /F4 12.0 Tf  [(Links)] TJ ET
BT 26.250 419.015 Td /F1 9.8 Tf  [(The commercial and university-based laboratories cited above are approved under the Clinical Laboratory Improvement )] TJ ET
BT 26.250 407.110 Td /F1 9.8 Tf  [(Amendments \(CLIA\). Several, but not all, are accredited by the College of American Pathologists \(CAP\). These assays are )] TJ ET
BT 26.250 395.205 Td /F1 9.8 Tf  [(developed and validated in-house, thus do not require FDA approval.)] TJ ET
BT 26.250 375.801 Td /F1 9.8 Tf  [(Relevant web sites:)] TJ ET
0.271 0.267 0.267 RG
40.337 359.364 m 
40.337 359.810 40.154 360.254 39.838 360.570 c
39.522 360.886 39.078 361.070 38.631 361.070 c
38.185 361.070 37.741 360.886 37.425 360.570 c
37.109 360.254 36.925 359.810 36.925 359.364 c
36.925 358.917 37.109 358.473 37.425 358.157 c
37.741 357.841 38.185 357.657 38.631 357.657 c
39.078 357.657 39.522 357.841 39.838 358.157 c
40.154 358.473 40.337 358.917 40.337 359.364 c f
BT 45.750 356.396 Td /F1 9.8 Tf  [(IRCCS Fondazione Salvatore Maugeri Molecular Cardiology Laboratories. Gene Connection for the Heart Inherited )] TJ ET
BT 45.750 344.491 Td /F1 9.8 Tf  [(Arrhythmias Database. )] TJ ET
0.267 0.267 0.267 rg
BT 147.618 344.491 Td /F1 9.8 Tf  [(www.fsm.it/cardmoc)] TJ ET
0.271 0.267 0.267 rg
BT 234.832 344.491 Td /F1 9.8 Tf  [(. Up-to-date compendium of inherited arrhythmia syndrome \(cardiac ion )] TJ ET
BT 45.750 332.586 Td /F1 9.8 Tf  [(channelopathy, arrhythmogenic right ventricular cardiomyopathy, and others\) mutations and polymorphisms, and condition )] TJ ET
BT 45.750 320.682 Td /F1 9.8 Tf  [(synopses.)] TJ ET
40.337 307.995 m 
40.337 308.441 40.154 308.885 39.838 309.201 c
39.522 309.517 39.078 309.701 38.631 309.701 c
38.185 309.701 37.741 309.517 37.425 309.201 c
37.109 308.885 36.925 308.441 36.925 307.995 c
36.925 307.548 37.109 307.104 37.425 306.788 c
37.741 306.472 38.185 306.288 38.631 306.288 c
39.078 306.288 39.522 306.472 39.838 306.788 c
40.154 307.104 40.337 307.548 40.337 307.995 c f
BT 45.750 305.027 Td /F1 9.8 Tf  [(Heart Rhythm Society.)] TJ ET
0.267 0.267 0.267 rg
BT 143.279 305.027 Td /F1 9.8 Tf  [( www.hrsonline.org)] TJ ET
0.271 0.267 0.267 rg
BT 226.174 305.027 Td /F1 9.8 Tf  [(. International society concerned with education and advocacy for cardiac )] TJ ET
BT 45.750 293.122 Td /F1 9.8 Tf  [(arrhythmia professionals and patients. Web site describes and provides access to professional educational programs, )] TJ ET
BT 45.750 281.217 Td /F1 9.8 Tf  [(clinical guidelines and consensus statements relating to diagnosis and management, and relevant legislation.)] TJ ET
40.337 268.530 m 
40.337 268.977 40.154 269.421 39.838 269.737 c
39.522 270.053 39.078 270.237 38.631 270.237 c
38.185 270.237 37.741 270.053 37.425 269.737 c
37.109 269.421 36.925 268.977 36.925 268.530 c
36.925 268.084 37.109 267.640 37.425 267.324 c
37.741 267.008 38.185 266.824 38.631 266.824 c
39.078 266.824 39.522 267.008 39.838 267.324 c
40.154 267.640 40.337 268.084 40.337 268.530 c f
BT 45.750 265.563 Td /F1 9.8 Tf  [(Cardiac Arrhythmias Research and Education \(CARE\) Foundation. )] TJ ET
0.267 0.267 0.267 rg
BT 336.729 265.563 Td /F1 9.8 Tf  [(www.longqt.com)] TJ ET
0.271 0.267 0.267 rg
BT 408.245 265.563 Td /F1 9.8 Tf  [(. Advocacy and awareness-raising )] TJ ET
BT 45.750 253.658 Td /F1 9.8 Tf  [(organization aimed at preventing sudden cardiac death due to acquired and heritable heart rhythm disorders. Web site )] TJ ET
BT 45.750 241.753 Td /F1 9.8 Tf  [(reports professional educational resources, and details emerging advocacy issues, support groups, and genetic testing )] TJ ET
BT 45.750 229.848 Td /F1 9.8 Tf  [(laboratories.)] TJ ET
40.337 217.161 m 
40.337 217.608 40.154 218.052 39.838 218.368 c
39.522 218.684 39.078 218.868 38.631 218.868 c
38.185 218.868 37.741 218.684 37.425 218.368 c
37.109 218.052 36.925 217.608 36.925 217.161 c
36.925 216.715 37.109 216.271 37.425 215.955 c
37.741 215.639 38.185 215.455 38.631 215.455 c
39.078 215.455 39.522 215.639 39.838 215.955 c
40.154 216.271 40.337 216.715 40.337 217.161 c f
BT 45.750 214.194 Td /F1 9.8 Tf  [(Sudden Arrhythmia Death Syndromes Foundation. )] TJ ET
0.267 0.267 0.267 rg
BT 266.851 214.194 Td /F1 9.8 Tf  [(www.sads.org)] TJ ET
0.271 0.267 0.267 rg
BT 328.071 214.194 Td /F1 9.8 Tf  [(. Aimed at preventing sudden and unexpected cardiac )] TJ ET
BT 45.750 202.289 Td /F1 9.8 Tf  [(death in children and young adults, the Foundation�s web site describes public awareness-raising activities, advocacy )] TJ ET
BT 45.750 190.384 Td /F1 9.8 Tf  [(initiatives impacting patients and professionals, and patient and family support services.)] TJ ET
40.337 177.697 m 
40.337 178.144 40.154 178.588 39.838 178.904 c
39.522 179.219 39.078 179.403 38.631 179.403 c
38.185 179.403 37.741 179.219 37.425 178.904 c
37.109 178.588 36.925 178.144 36.925 177.697 c
36.925 177.250 37.109 176.806 37.425 176.490 c
37.741 176.175 38.185 175.991 38.631 175.991 c
39.078 175.991 39.522 176.175 39.838 176.490 c
40.154 176.806 40.337 177.250 40.337 177.697 c f
BT 45.750 174.729 Td /F1 9.8 Tf  [(Drugs that Prolong the QT Interval and/or Induce Torsades de Pointes Ventricular Arrhythmia.)] TJ ET
0.267 0.267 0.267 rg
BT 450.550 174.729 Td /F1 9.8 Tf  [( www.qtdrugs.org)] TJ ET
0.271 0.267 0.267 rg
BT 526.406 174.729 Td /F1 9.8 Tf  [(. Web site )] TJ ET
BT 45.750 162.825 Td /F1 9.8 Tf  [(provides a comprehensive list of arrhythmogenic drugs to be avoided by LQTS patients, lists drugs by risk group, provides )] TJ ET
BT 45.750 150.920 Td /F1 9.8 Tf  [(consumer education tools, and describes the drug-induced arrhythmias case registry.)] TJ ET
40.337 138.233 m 
40.337 138.679 40.154 139.123 39.838 139.439 c
39.522 139.755 39.078 139.939 38.631 139.939 c
38.185 139.939 37.741 139.755 37.425 139.439 c
37.109 139.123 36.925 138.679 36.925 138.233 c
36.925 137.786 37.109 137.342 37.425 137.026 c
37.741 136.710 38.185 136.527 38.631 136.527 c
39.078 136.527 39.522 136.710 39.838 137.026 c
40.154 137.342 40.337 137.786 40.337 138.233 c f
BT 45.750 135.265 Td /F1 9.8 Tf  [(Raymond Brugada Senior Foundation, )] TJ ET
0.267 0.267 0.267 rg
BT 214.834 135.265 Td /F1 9.8 Tf  [(www.brugada.org)] TJ ET
0.271 0.267 0.267 rg
BT 291.236 135.265 Td /F1 9.8 Tf  [(. Foundation web site provides a full description of Brugada )] TJ ET
BT 45.750 123.360 Td /F1 9.8 Tf  [(syndrome, cites relevant literature and professional policies, and offers avenues for partnering in research and joining a )] TJ ET
BT 45.750 111.456 Td /F1 9.8 Tf  [(support group.)] TJ ET
40.337 98.769 m 
40.337 99.215 40.154 99.659 39.838 99.975 c
39.522 100.291 39.078 100.475 38.631 100.475 c
38.185 100.475 37.741 100.291 37.425 99.975 c
37.109 99.659 36.925 99.215 36.925 98.769 c
36.925 98.322 37.109 97.878 37.425 97.562 c
37.741 97.246 38.185 97.062 38.631 97.062 c
39.078 97.062 39.522 97.246 39.838 97.562 c
40.154 97.878 40.337 98.322 40.337 98.769 c f
BT 45.750 95.801 Td /F1 9.8 Tf  [(BrugadaDrugs.org. )] TJ ET
0.267 0.267 0.267 rg
BT 130.829 95.801 Td /F1 9.8 Tf  [(www.brugadadrugs.org)] TJ ET
0.271 0.267 0.267 rg
BT 231.614 95.801 Td /F1 9.8 Tf  [(. Web site provides a comprehensive list of arrhythmogenic drugs to be avoided )] TJ ET
BT 45.750 83.896 Td /F1 9.8 Tf  [(by Brudaga syndrome patients, lists drugs by risk group, cites drugs diagnostic for Brs, and offers a patient letter listing )] TJ ET
BT 45.750 71.991 Td /F1 9.8 Tf  [(drugs to be avoided.)] TJ ET
Q
q
15.000 21.209 577.500 755.791 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F1 9.8 Tf  [(found the highest yield \(64%\) and lowest cost \($8,418 per positive genotyping\) for patients with ECG-confirmed LQTS, but )] TJ ET
BT 26.250 755.571 Td /F1 9.8 Tf  [(diminishing yields and increasing costs for patients with borderline QTc intervals and those with normal intervals but a positive )] TJ ET
BT 26.250 743.667 Td /F1 9.8 Tf  [(family history for SCD)] TJ ET
0.267 0.267 0.267 rg
BT 120.513 745.174 Td /F4 8.7 Tf  [(60)] TJ ET
0.271 0.267 0.267 rg
BT 130.150 743.667 Td /F1 9.8 Tf  [(. They recommended genetic testing be prioritized to those with a �conclusive diagnosis� of LQTS. )] TJ ET
BT 26.250 731.762 Td /F1 9.8 Tf  [(Genotyping of individuals with a conclusive diagnosis of CPVT, and of patients with type 1 BrS ECG with atrioventricular block )] TJ ET
BT 26.250 719.857 Td /F1 9.8 Tf  [(was also found to be cost-effective. Apart from this report, the host of cost-effectiveness analyses for Brugada syndrome deal )] TJ ET
BT 26.250 707.952 Td /F1 9.8 Tf  [(with the issue of implantation of ICDs.)] TJ ET
BT 26.250 688.548 Td /F1 9.8 Tf  [(Perez et al. used a Markov model to assess the cost-effectiveness of different strategies for testing then treating an )] TJ ET
BT 26.250 676.643 Td /F1 9.8 Tf  [(asymptomatic 10 year-old first degree relative of a patient with clinically evident LQTS)] TJ ET
0.267 0.267 0.267 rg
BT 395.804 678.150 Td /F4 8.7 Tf  [(75)] TJ ET
0.271 0.267 0.267 rg
BT 405.442 676.643 Td /F1 9.8 Tf  [(. They concluded that genetic testing is )] TJ ET
BT 26.250 664.738 Td /F1 9.8 Tf  [(moderately expensive, at $67,400 per quality adjusted life year saved, but improves with higher clinical suspicion of the )] TJ ET
BT 26.250 652.833 Td /F1 9.8 Tf  [(proband, number of relatives tested, and stronger family history of sudden death.)] TJ ET
BT 26.250 633.429 Td /F1 9.8 Tf  [(CGT is covered to different extents by insurance providers, ranging from denial to 100% coverage, with most covering at least )] TJ ET
BT 26.250 621.524 Td /F1 9.8 Tf  [(50 to 75% of the cost)] TJ ET
0.267 0.267 0.267 rg
BT 117.851 623.031 Td /F4 8.7 Tf  [(22)] TJ ET
0.271 0.267 0.267 rg
BT 127.489 621.524 Td /F1 9.8 Tf  [(. Some health plan policies explicitly limit genetic test reimbursement to LQTS while excluding the other )] TJ ET
BT 26.250 609.619 Td /F1 9.8 Tf  [(channelopathies)] TJ ET
0.267 0.267 0.267 rg
BT 97.249 611.126 Td /F4 8.7 Tf  [(76)] TJ ET
0.271 0.267 0.267 rg
BT 106.887 609.619 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 590.214 Td /F5 9.8 Tf  [(Public Health Ethical, Legal, and Social \(PHELSI\) Considerations:)] TJ ET
BT 26.250 570.810 Td /F1 9.8 Tf  [(Genetic testing for cardiac channelopathies is laden with ethical issues, including the search for a balance between individual )] TJ ET
BT 26.250 558.905 Td /F1 9.8 Tf  [(privacy vs. alerting at-risk family members, as well as psychosocial issues inherent in informing individuals of their risk)] TJ ET
0.267 0.267 0.267 rg
BT 534.469 560.412 Td /F4 8.7 Tf  [(1)] TJ ET
BT 539.287 560.412 Td /F4 8.7 Tf  [(77)] TJ ET
BT 548.925 560.412 Td /F4 8.7 Tf  [(78)] TJ ET
0.271 0.267 0.267 rg
BT 558.562 558.905 Td /F1 9.8 Tf  [(. A )] TJ ET
BT 26.250 547.000 Td /F1 9.8 Tf  [(review by Wren provides general recommendations for genetic testing of children in families with a history of SCD, and offers )] TJ ET
BT 26.250 535.095 Td /F1 9.8 Tf  [(ethical considerations in childhood genetic testing for Brugada syndrome)] TJ ET
0.267 0.267 0.267 rg
BT 339.478 536.603 Td /F4 8.7 Tf  [(79)] TJ ET
0.271 0.267 0.267 rg
BT 349.116 535.095 Td /F1 9.8 Tf  [(. Use of pacemakers and ICDs in children, while )] TJ ET
BT 26.250 523.191 Td /F1 9.8 Tf  [(often done under situations of medical necessity, can involve trade-offs between benefit and adverse effects)] TJ ET
0.267 0.267 0.267 rg
BT 491.783 524.698 Td /F4 8.7 Tf  [(45)] TJ ET
BT 501.421 524.698 Td /F4 8.7 Tf  [(69)] TJ ET
BT 511.058 524.698 Td /F4 8.7 Tf  [(80)] TJ ET
0.271 0.267 0.267 rg
BT 520.695 523.191 Td /F1 9.8 Tf  [(. Screening )] TJ ET
BT 26.250 511.286 Td /F1 9.8 Tf  [(for LQTS mutations in particular racial-ethnic groups deserves further ethical analysis)] TJ ET
0.267 0.267 0.267 rg
BT 393.630 512.793 Td /F4 8.7 Tf  [(21)] TJ ET
0.271 0.267 0.267 rg
BT 403.267 511.286 Td /F1 9.8 Tf  [(. Personalization of drug treatment )] TJ ET
BT 26.250 499.381 Td /F1 9.8 Tf  [(through determination of individually specific genotype remains a hoped-for future direction in the field)] TJ ET
0.267 0.267 0.267 rg
BT 464.659 500.888 Td /F4 8.7 Tf  [(1)] TJ ET
BT 469.477 500.888 Td /F4 8.7 Tf  [(75)] TJ ET
0.271 0.267 0.267 rg
BT 479.115 499.381 Td /F1 9.8 Tf  [(. Risk assessment for )] TJ ET
BT 26.250 487.476 Td /F1 9.8 Tf  [(inherited heart arrhythmias is also becoming a part of direct-to-consumer genetic testing, an area subject to increasing attention )] TJ ET
BT 26.250 475.572 Td /F1 9.8 Tf  [(by policy makers.)] TJ ET
BT 26.250 438.969 Td /F4 12.0 Tf  [(Links)] TJ ET
BT 26.250 419.015 Td /F1 9.8 Tf  [(The commercial and university-based laboratories cited above are approved under the Clinical Laboratory Improvement )] TJ ET
BT 26.250 407.110 Td /F1 9.8 Tf  [(Amendments \(CLIA\). Several, but not all, are accredited by the College of American Pathologists \(CAP\). These assays are )] TJ ET
BT 26.250 395.205 Td /F1 9.8 Tf  [(developed and validated in-house, thus do not require FDA approval.)] TJ ET
BT 26.250 375.801 Td /F1 9.8 Tf  [(Relevant web sites:)] TJ ET
0.271 0.267 0.267 RG
40.337 359.364 m 
40.337 359.810 40.154 360.254 39.838 360.570 c
39.522 360.886 39.078 361.070 38.631 361.070 c
38.185 361.070 37.741 360.886 37.425 360.570 c
37.109 360.254 36.925 359.810 36.925 359.364 c
36.925 358.917 37.109 358.473 37.425 358.157 c
37.741 357.841 38.185 357.657 38.631 357.657 c
39.078 357.657 39.522 357.841 39.838 358.157 c
40.154 358.473 40.337 358.917 40.337 359.364 c f
BT 45.750 356.396 Td /F1 9.8 Tf  [(IRCCS Fondazione Salvatore Maugeri Molecular Cardiology Laboratories. Gene Connection for the Heart Inherited )] TJ ET
BT 45.750 344.491 Td /F1 9.8 Tf  [(Arrhythmias Database. )] TJ ET
0.267 0.267 0.267 rg
BT 147.618 344.491 Td /F1 9.8 Tf  [(www.fsm.it/cardmoc)] TJ ET
0.271 0.267 0.267 rg
BT 234.832 344.491 Td /F1 9.8 Tf  [(. Up-to-date compendium of inherited arrhythmia syndrome \(cardiac ion )] TJ ET
BT 45.750 332.586 Td /F1 9.8 Tf  [(channelopathy, arrhythmogenic right ventricular cardiomyopathy, and others\) mutations and polymorphisms, and condition )] TJ ET
BT 45.750 320.682 Td /F1 9.8 Tf  [(synopses.)] TJ ET
40.337 307.995 m 
40.337 308.441 40.154 308.885 39.838 309.201 c
39.522 309.517 39.078 309.701 38.631 309.701 c
38.185 309.701 37.741 309.517 37.425 309.201 c
37.109 308.885 36.925 308.441 36.925 307.995 c
36.925 307.548 37.109 307.104 37.425 306.788 c
37.741 306.472 38.185 306.288 38.631 306.288 c
39.078 306.288 39.522 306.472 39.838 306.788 c
40.154 307.104 40.337 307.548 40.337 307.995 c f
BT 45.750 305.027 Td /F1 9.8 Tf  [(Heart Rhythm Society.)] TJ ET
0.267 0.267 0.267 rg
BT 143.279 305.027 Td /F1 9.8 Tf  [( www.hrsonline.org)] TJ ET
0.271 0.267 0.267 rg
BT 226.174 305.027 Td /F1 9.8 Tf  [(. International society concerned with education and advocacy for cardiac )] TJ ET
BT 45.750 293.122 Td /F1 9.8 Tf  [(arrhythmia professionals and patients. Web site describes and provides access to professional educational programs, )] TJ ET
BT 45.750 281.217 Td /F1 9.8 Tf  [(clinical guidelines and consensus statements relating to diagnosis and management, and relevant legislation.)] TJ ET
40.337 268.530 m 
40.337 268.977 40.154 269.421 39.838 269.737 c
39.522 270.053 39.078 270.237 38.631 270.237 c
38.185 270.237 37.741 270.053 37.425 269.737 c
37.109 269.421 36.925 268.977 36.925 268.530 c
36.925 268.084 37.109 267.640 37.425 267.324 c
37.741 267.008 38.185 266.824 38.631 266.824 c
39.078 266.824 39.522 267.008 39.838 267.324 c
40.154 267.640 40.337 268.084 40.337 268.530 c f
BT 45.750 265.563 Td /F1 9.8 Tf  [(Cardiac Arrhythmias Research and Education \(CARE\) Foundation. )] TJ ET
0.267 0.267 0.267 rg
BT 336.729 265.563 Td /F1 9.8 Tf  [(www.longqt.com)] TJ ET
0.271 0.267 0.267 rg
BT 408.245 265.563 Td /F1 9.8 Tf  [(. Advocacy and awareness-raising )] TJ ET
BT 45.750 253.658 Td /F1 9.8 Tf  [(organization aimed at preventing sudden cardiac death due to acquired and heritable heart rhythm disorders. Web site )] TJ ET
BT 45.750 241.753 Td /F1 9.8 Tf  [(reports professional educational resources, and details emerging advocacy issues, support groups, and genetic testing )] TJ ET
BT 45.750 229.848 Td /F1 9.8 Tf  [(laboratories.)] TJ ET
40.337 217.161 m 
40.337 217.608 40.154 218.052 39.838 218.368 c
39.522 218.684 39.078 218.868 38.631 218.868 c
38.185 218.868 37.741 218.684 37.425 218.368 c
37.109 218.052 36.925 217.608 36.925 217.161 c
36.925 216.715 37.109 216.271 37.425 215.955 c
37.741 215.639 38.185 215.455 38.631 215.455 c
39.078 215.455 39.522 215.639 39.838 215.955 c
40.154 216.271 40.337 216.715 40.337 217.161 c f
BT 45.750 214.194 Td /F1 9.8 Tf  [(Sudden Arrhythmia Death Syndromes Foundation. )] TJ ET
0.267 0.267 0.267 rg
BT 266.851 214.194 Td /F1 9.8 Tf  [(www.sads.org)] TJ ET
0.271 0.267 0.267 rg
BT 328.071 214.194 Td /F1 9.8 Tf  [(. Aimed at preventing sudden and unexpected cardiac )] TJ ET
BT 45.750 202.289 Td /F1 9.8 Tf  [(death in children and young adults, the Foundation�s web site describes public awareness-raising activities, advocacy )] TJ ET
BT 45.750 190.384 Td /F1 9.8 Tf  [(initiatives impacting patients and professionals, and patient and family support services.)] TJ ET
40.337 177.697 m 
40.337 178.144 40.154 178.588 39.838 178.904 c
39.522 179.219 39.078 179.403 38.631 179.403 c
38.185 179.403 37.741 179.219 37.425 178.904 c
37.109 178.588 36.925 178.144 36.925 177.697 c
36.925 177.250 37.109 176.806 37.425 176.490 c
37.741 176.175 38.185 175.991 38.631 175.991 c
39.078 175.991 39.522 176.175 39.838 176.490 c
40.154 176.806 40.337 177.250 40.337 177.697 c f
BT 45.750 174.729 Td /F1 9.8 Tf  [(Drugs that Prolong the QT Interval and/or Induce Torsades de Pointes Ventricular Arrhythmia.)] TJ ET
0.267 0.267 0.267 rg
BT 450.550 174.729 Td /F1 9.8 Tf  [( www.qtdrugs.org)] TJ ET
0.271 0.267 0.267 rg
BT 526.406 174.729 Td /F1 9.8 Tf  [(. Web site )] TJ ET
BT 45.750 162.825 Td /F1 9.8 Tf  [(provides a comprehensive list of arrhythmogenic drugs to be avoided by LQTS patients, lists drugs by risk group, provides )] TJ ET
BT 45.750 150.920 Td /F1 9.8 Tf  [(consumer education tools, and describes the drug-induced arrhythmias case registry.)] TJ ET
40.337 138.233 m 
40.337 138.679 40.154 139.123 39.838 139.439 c
39.522 139.755 39.078 139.939 38.631 139.939 c
38.185 139.939 37.741 139.755 37.425 139.439 c
37.109 139.123 36.925 138.679 36.925 138.233 c
36.925 137.786 37.109 137.342 37.425 137.026 c
37.741 136.710 38.185 136.527 38.631 136.527 c
39.078 136.527 39.522 136.710 39.838 137.026 c
40.154 137.342 40.337 137.786 40.337 138.233 c f
BT 45.750 135.265 Td /F1 9.8 Tf  [(Raymond Brugada Senior Foundation, )] TJ ET
0.267 0.267 0.267 rg
BT 214.834 135.265 Td /F1 9.8 Tf  [(www.brugada.org)] TJ ET
0.271 0.267 0.267 rg
BT 291.236 135.265 Td /F1 9.8 Tf  [(. Foundation web site provides a full description of Brugada )] TJ ET
BT 45.750 123.360 Td /F1 9.8 Tf  [(syndrome, cites relevant literature and professional policies, and offers avenues for partnering in research and joining a )] TJ ET
BT 45.750 111.456 Td /F1 9.8 Tf  [(support group.)] TJ ET
40.337 98.769 m 
40.337 99.215 40.154 99.659 39.838 99.975 c
39.522 100.291 39.078 100.475 38.631 100.475 c
38.185 100.475 37.741 100.291 37.425 99.975 c
37.109 99.659 36.925 99.215 36.925 98.769 c
36.925 98.322 37.109 97.878 37.425 97.562 c
37.741 97.246 38.185 97.062 38.631 97.062 c
39.078 97.062 39.522 97.246 39.838 97.562 c
40.154 97.878 40.337 98.322 40.337 98.769 c f
BT 45.750 95.801 Td /F1 9.8 Tf  [(BrugadaDrugs.org. )] TJ ET
0.267 0.267 0.267 rg
BT 130.829 95.801 Td /F1 9.8 Tf  [(www.brugadadrugs.org)] TJ ET
0.271 0.267 0.267 rg
BT 231.614 95.801 Td /F1 9.8 Tf  [(. Web site provides a comprehensive list of arrhythmogenic drugs to be avoided )] TJ ET
BT 45.750 83.896 Td /F1 9.8 Tf  [(by Brudaga syndrome patients, lists drugs by risk group, cites drugs diagnostic for Brs, and offers a patient letter listing )] TJ ET
BT 45.750 71.991 Td /F1 9.8 Tf  [(drugs to be avoided.)] TJ ET
Q
q
0.000 0.000 0.000 rg
BT 291.710 19.825 Td /F1 11.0 Tf  [(5)] TJ ET
BT 25.000 19.825 Td /F1 11.0 Tf  [(PLOS Currents Evidence on Genomic Tests)] TJ ET

Q
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BT 26.250 241.625 Td /F1 9.8 Tf  [(Epub 2008 Apr 21. PubMed PMID: 18427136.)] TJ ET
BT 26.250 222.220 Td /F1 9.8 Tf  [(11.)] TJ ET
BT 43.553 222.220 Td /F1 9.8 Tf  [(Moss AJ, Goldenberg I. Importance of Knowing the Genotype and the Specific Mutation When Managing Patients with Long )] TJ ET
BT 26.250 210.315 Td /F1 9.8 Tf  [(QT Syndrome. Circ Arrhythm Electrophysiol. 2008 Aug;1\(3\):213-26; discussion 226. Review. PubMed PMID: 19701491; )] TJ ET
BT 26.250 198.411 Td /F1 9.8 Tf  [(PubMed Central PMCID: PMC2729934.)] TJ ET
BT 26.250 179.006 Td /F1 9.8 Tf  [(12.)] TJ ET
BT 43.553 179.006 Td /F1 9.8 Tf  [(Hobbs JB, Peterson DR, Moss AJ, McNitt S, Zareba W, Goldenberg I, Qi M, Robinson JL, Sauer AJ, Ackerman MJ, )] TJ ET
BT 26.250 167.101 Td /F1 9.8 Tf  [(Benhorin J, Kaufman ES, Locati EH, Napolitano C, Priori SG, Towbin JA, Vincent GM, Zhang L. Risk of aborted cardiac arrest )] TJ ET
BT 26.250 155.196 Td /F1 9.8 Tf  [(or sudden cardiac death during adolescence in the long-QT syndrome. JAMA. 2006 Sep 13;296\(10\):1249-54. PubMed PMID: )] TJ ET
BT 26.250 143.292 Td /F1 9.8 Tf  [(16968849.)] TJ ET
BT 26.250 123.887 Td /F1 9.8 Tf  [(13.)] TJ ET
BT 43.553 123.887 Td /F1 9.8 Tf  [(Moss AJ, Zareba W, Hall WJ, Schwartz PJ, Crampton RS, Benhorin J, Vincent GM, Locati EH, Priori SG, Napolitano C, )] TJ ET
BT 26.250 111.982 Td /F1 9.8 Tf  [(Medina A, Zhang L, Robinson JL, Timothy K, Towbin JA, Andrews ML. Effectiveness and limitations of beta-blocker therapy in )] TJ ET
BT 26.250 100.077 Td /F1 9.8 Tf  [(congenital long-QT syndrome. Circulation. 2000 Feb 15;101\(6\):616-23. PubMed PMID: 10673253.)] TJ ET
BT 26.250 80.673 Td /F1 9.8 Tf  [(14.)] TJ ET
BT 43.553 80.673 Td /F1 9.8 Tf  [(National Center for Biotechnology Information \(NCBI\). Long QT syndrome 1: clinical laboratories. Available at: )] TJ ET
BT 26.250 68.768 Td /F1 9.8 Tf  [(https://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/clinical_disease_id/115871?db=genetests. Accessed 28 Apr 2011.)] TJ ET
BT 26.250 49.363 Td /F1 9.8 Tf  [(15.)] TJ ET
BT 43.553 49.363 Td /F1 9.8 Tf  [(Tzou WS, Gerstenfeld EP. Genetic testing in the management of inherited arrhythmia syndromes. Curr Cardiol Rep. 2009 )] TJ ET
Q
q
15.000 35.077 577.500 741.923 re W n
0.271 0.267 0.267 rg
BT 26.250 750.278 Td /F4 12.0 Tf  [(Competing Interests)] TJ ET
BT 26.250 730.324 Td /F1 9.8 Tf  [(The authors have declared that no competing interests exist.)] TJ ET
BT 26.250 693.722 Td /F4 12.0 Tf  [(References)] TJ ET
BT 26.250 666.267 Td /F1 9.8 Tf  [(1.)] TJ ET
BT 38.132 666.267 Td /F1 9.8 Tf  [(Tester DJ, Ackerman MJ. Genetic testing for potentially lethal, highly treatable inherited cardiomyopathies/channelopathies in )] TJ ET
BT 26.250 654.363 Td /F1 9.8 Tf  [(clinical practice. Circulation. 2011 Mar 8;123\(9\):1021-37. Review. PubMed PMID: 21382904; PubMed Central PMCID: )] TJ ET
BT 26.250 642.458 Td /F1 9.8 Tf  [(PMC3073829.)] TJ ET
BT 26.250 623.053 Td /F1 9.8 Tf  [(2.)] TJ ET
BT 38.132 623.053 Td /F1 9.8 Tf  [(Benito B, Brugada R, Brugada J, Brugada P. Brugada syndrome. Prog Cardiovasc Dis. 2008 Jul-Aug;51\(1\):1-22. Review. )] TJ ET
BT 26.250 611.148 Td /F1 9.8 Tf  [(PubMed PMID: 18634914.)] TJ ET
BT 26.250 591.744 Td /F1 9.8 Tf  [(3.)] TJ ET
BT 38.132 591.744 Td /F1 9.8 Tf  [(Heart Rhythm UK Familial Sudden Death Syndromes Statement Development Group. Clinical indications for genetic testing )] TJ ET
BT 26.250 579.839 Td /F1 9.8 Tf  [(in familial sudden cardiac death syndromes: an HRUK position statement. Heart. 2008 Apr;94\(4\):502-7. Epub 2007 Jul 30. )] TJ ET
BT 26.250 567.934 Td /F1 9.8 Tf  [(PubMed PMID: 17664186.)] TJ ET
BT 26.250 548.529 Td /F1 9.8 Tf  [(4.)] TJ ET
BT 38.132 548.529 Td /F1 9.8 Tf  [(Moss AJ. Long QT Syndrome. JAMA. 2003 Apr 23-30;289\(16\):2041-4. Review. PubMed PMID: 12709446.)] TJ ET
BT 26.250 529.125 Td /F1 9.8 Tf  [(5.)] TJ ET
BT 38.132 529.125 Td /F1 9.8 Tf  [(Priori SG, Napolitano C, Memmi M, Colombi B, Drago F, Gasparini M, DeSimone L, Coltorti F, Bloise R, Keegan R, Cruz )] TJ ET
BT 26.250 517.220 Td /F1 9.8 Tf  [(Filho FE, Vignati G, Benatar A, DeLogu A. Clinical and molecular characterization of patients with catecholaminergic )] TJ ET
BT 26.250 505.315 Td /F1 9.8 Tf  [(polymorphic ventricular tachycardia. Circulation. 2002 Jul 2;106\(1\):69-74. PubMed PMID: 12093772.)] TJ ET
BT 26.250 485.910 Td /F1 9.8 Tf  [(6.)] TJ ET
BT 38.132 485.910 Td /F1 9.8 Tf  [(Ackerman MJ, Priori SG, Willems S, Berul C, Brugada R, Calkins H, Camm AJ, Ellinor PT, Gollob M, Hamilton R, )] TJ ET
BT 26.250 474.006 Td /F1 9.8 Tf  [(Hershberger RE, Judge DP, Le Marec H, McKenna WJ, Schulze-Bahr E, Semsarian C, Towbin JA, Watkins H, Wilde A, Wolpert )] TJ ET
BT 26.250 462.101 Td /F1 9.8 Tf  [(C, Zipes DP. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and )] TJ ET
BT 26.250 450.196 Td /F1 9.8 Tf  [(cardiomyopathies this document was developed as a partnership between the Heart Rhythm Society \(HRS\) and the European )] TJ ET
BT 26.250 438.291 Td /F1 9.8 Tf  [(Heart Rhythm Association \(EHRA\). Heart Rhythm. 2011 Aug;8\(8\):1308-39. PubMed PMID: 21787999.)] TJ ET
BT 26.250 418.887 Td /F1 9.8 Tf  [(7.)] TJ ET
BT 38.132 418.887 Td /F1 9.8 Tf  [(Medeiros-Domingo A, Bhuiyan ZA, Tester DJ, Hofman N, Bikker H, van Tintelen JP, Mannens MM, Wilde AA, Ackerman MJ. )] TJ ET
BT 26.250 406.982 Td /F1 9.8 Tf  [(The RYR2-encoded ryanodine receptor/calcium release channel in patients diagnosed previously with either catecholaminergic )] TJ ET
BT 26.250 395.077 Td /F1 9.8 Tf  [(polymorphic ventricular tachycardia or genotype negative, exercise-induced long QT syndrome: a comprehensive open reading )] TJ ET
BT 26.250 383.172 Td /F1 9.8 Tf  [(frame mutational analysis. J Am Coll Cardiol. 2009 Nov 24;54\(22\):2065-74. PubMed PMID: 19926015; PubMed Central PMCID: )] TJ ET
BT 26.250 371.268 Td /F1 9.8 Tf  [(PMC2880864.)] TJ ET
BT 26.250 351.863 Td /F1 9.8 Tf  [(8.)] TJ ET
BT 38.132 351.863 Td /F1 9.8 Tf  [(Takenaka K, Ai T, Shimizu W, Kobori A, Ninomiya T, Otani H, Kubota T, Takaki H, Kamakura S, Horie M. Exercise stress test )] TJ ET
BT 26.250 339.958 Td /F1 9.8 Tf  [(amplifies genotype-phenotype correlation in the LQT1 and LQT2 forms of the long-QT syndrome. Circulation. 2003 Feb )] TJ ET
BT 26.250 328.053 Td /F1 9.8 Tf  [(18;107\(6\):838-44. PubMed PMID: 12591753.)] TJ ET
BT 26.250 308.649 Td /F1 9.8 Tf  [(9.)] TJ ET
BT 38.132 308.649 Td /F1 9.8 Tf  [(Hofman N, Tan HL, Alders M, van Langen IM, Wilde AA. Active cascade screening in primary inherited arrhythmia )] TJ ET
BT 26.250 296.744 Td /F1 9.8 Tf  [(syndromes: does it lead to prophylactic treatment? J Am Coll Cardiol. 2010 Jun 8;55\(23\):2570-6. PubMed PMID: 20513597.)] TJ ET
BT 26.250 277.339 Td /F1 9.8 Tf  [(10.)] TJ ET
BT 43.553 277.339 Td /F1 9.8 Tf  [(Goldenberg I, Moss AJ, Peterson DR, McNitt S, Zareba W, Andrews ML, Robinson JL, Locati EH, Ackerman MJ, Benhorin )] TJ ET
BT 26.250 265.434 Td /F1 9.8 Tf  [(J, Kaufman ES, Napolitano C, Priori SG, Qi M, Schwartz PJ, Towbin JA, Vincent GM, Zhang L. Risk factors for aborted cardiac )] TJ ET
BT 26.250 253.530 Td /F1 9.8 Tf  [(arrest and sudden cardiac death in children with the congenital long-QT syndrome. Circulation. 2008 Apr 29;117\(17\):2184-91. )] TJ ET
BT 26.250 241.625 Td /F1 9.8 Tf  [(Epub 2008 Apr 21. PubMed PMID: 18427136.)] TJ ET
BT 26.250 222.220 Td /F1 9.8 Tf  [(11.)] TJ ET
BT 43.553 222.220 Td /F1 9.8 Tf  [(Moss AJ, Goldenberg I. Importance of Knowing the Genotype and the Specific Mutation When Managing Patients with Long )] TJ ET
BT 26.250 210.315 Td /F1 9.8 Tf  [(QT Syndrome. Circ Arrhythm Electrophysiol. 2008 Aug;1\(3\):213-26; discussion 226. Review. PubMed PMID: 19701491; )] TJ ET
BT 26.250 198.411 Td /F1 9.8 Tf  [(PubMed Central PMCID: PMC2729934.)] TJ ET
BT 26.250 179.006 Td /F1 9.8 Tf  [(12.)] TJ ET
BT 43.553 179.006 Td /F1 9.8 Tf  [(Hobbs JB, Peterson DR, Moss AJ, McNitt S, Zareba W, Goldenberg I, Qi M, Robinson JL, Sauer AJ, Ackerman MJ, )] TJ ET
BT 26.250 167.101 Td /F1 9.8 Tf  [(Benhorin J, Kaufman ES, Locati EH, Napolitano C, Priori SG, Towbin JA, Vincent GM, Zhang L. Risk of aborted cardiac arrest )] TJ ET
BT 26.250 155.196 Td /F1 9.8 Tf  [(or sudden cardiac death during adolescence in the long-QT syndrome. JAMA. 2006 Sep 13;296\(10\):1249-54. PubMed PMID: )] TJ ET
BT 26.250 143.292 Td /F1 9.8 Tf  [(16968849.)] TJ ET
BT 26.250 123.887 Td /F1 9.8 Tf  [(13.)] TJ ET
BT 43.553 123.887 Td /F1 9.8 Tf  [(Moss AJ, Zareba W, Hall WJ, Schwartz PJ, Crampton RS, Benhorin J, Vincent GM, Locati EH, Priori SG, Napolitano C, )] TJ ET
BT 26.250 111.982 Td /F1 9.8 Tf  [(Medina A, Zhang L, Robinson JL, Timothy K, Towbin JA, Andrews ML. Effectiveness and limitations of beta-blocker therapy in )] TJ ET
BT 26.250 100.077 Td /F1 9.8 Tf  [(congenital long-QT syndrome. Circulation. 2000 Feb 15;101\(6\):616-23. PubMed PMID: 10673253.)] TJ ET
BT 26.250 80.673 Td /F1 9.8 Tf  [(14.)] TJ ET
BT 43.553 80.673 Td /F1 9.8 Tf  [(National Center for Biotechnology Information \(NCBI\). Long QT syndrome 1: clinical laboratories. Available at: )] TJ ET
BT 26.250 68.768 Td /F1 9.8 Tf  [(https://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/clinical_disease_id/115871?db=genetests. Accessed 28 Apr 2011.)] TJ ET
BT 26.250 49.363 Td /F1 9.8 Tf  [(15.)] TJ ET
BT 43.553 49.363 Td /F1 9.8 Tf  [(Tzou WS, Gerstenfeld EP. Genetic testing in the management of inherited arrhythmia syndromes. Curr Cardiol Rep. 2009 )] TJ ET
Q
q
15.000 35.077 577.500 741.923 re W n
0.271 0.267 0.267 rg
BT 26.250 750.278 Td /F4 12.0 Tf  [(Competing Interests)] TJ ET
BT 26.250 730.324 Td /F1 9.8 Tf  [(The authors have declared that no competing interests exist.)] TJ ET
BT 26.250 693.722 Td /F4 12.0 Tf  [(References)] TJ ET
BT 26.250 666.267 Td /F1 9.8 Tf  [(1.)] TJ ET
BT 38.132 666.267 Td /F1 9.8 Tf  [(Tester DJ, Ackerman MJ. Genetic testing for potentially lethal, highly treatable inherited cardiomyopathies/channelopathies in )] TJ ET
BT 26.250 654.363 Td /F1 9.8 Tf  [(clinical practice. Circulation. 2011 Mar 8;123\(9\):1021-37. Review. PubMed PMID: 21382904; PubMed Central PMCID: )] TJ ET
BT 26.250 642.458 Td /F1 9.8 Tf  [(PMC3073829.)] TJ ET
BT 26.250 623.053 Td /F1 9.8 Tf  [(2.)] TJ ET
BT 38.132 623.053 Td /F1 9.8 Tf  [(Benito B, Brugada R, Brugada J, Brugada P. Brugada syndrome. Prog Cardiovasc Dis. 2008 Jul-Aug;51\(1\):1-22. Review. )] TJ ET
BT 26.250 611.148 Td /F1 9.8 Tf  [(PubMed PMID: 18634914.)] TJ ET
BT 26.250 591.744 Td /F1 9.8 Tf  [(3.)] TJ ET
BT 38.132 591.744 Td /F1 9.8 Tf  [(Heart Rhythm UK Familial Sudden Death Syndromes Statement Development Group. Clinical indications for genetic testing )] TJ ET
BT 26.250 579.839 Td /F1 9.8 Tf  [(in familial sudden cardiac death syndromes: an HRUK position statement. Heart. 2008 Apr;94\(4\):502-7. Epub 2007 Jul 30. )] TJ ET
BT 26.250 567.934 Td /F1 9.8 Tf  [(PubMed PMID: 17664186.)] TJ ET
BT 26.250 548.529 Td /F1 9.8 Tf  [(4.)] TJ ET
BT 38.132 548.529 Td /F1 9.8 Tf  [(Moss AJ. Long QT Syndrome. JAMA. 2003 Apr 23-30;289\(16\):2041-4. Review. PubMed PMID: 12709446.)] TJ ET
BT 26.250 529.125 Td /F1 9.8 Tf  [(5.)] TJ ET
BT 38.132 529.125 Td /F1 9.8 Tf  [(Priori SG, Napolitano C, Memmi M, Colombi B, Drago F, Gasparini M, DeSimone L, Coltorti F, Bloise R, Keegan R, Cruz )] TJ ET
BT 26.250 517.220 Td /F1 9.8 Tf  [(Filho FE, Vignati G, Benatar A, DeLogu A. Clinical and molecular characterization of patients with catecholaminergic )] TJ ET
BT 26.250 505.315 Td /F1 9.8 Tf  [(polymorphic ventricular tachycardia. Circulation. 2002 Jul 2;106\(1\):69-74. PubMed PMID: 12093772.)] TJ ET
BT 26.250 485.910 Td /F1 9.8 Tf  [(6.)] TJ ET
BT 38.132 485.910 Td /F1 9.8 Tf  [(Ackerman MJ, Priori SG, Willems S, Berul C, Brugada R, Calkins H, Camm AJ, Ellinor PT, Gollob M, Hamilton R, )] TJ ET
BT 26.250 474.006 Td /F1 9.8 Tf  [(Hershberger RE, Judge DP, Le Marec H, McKenna WJ, Schulze-Bahr E, Semsarian C, Towbin JA, Watkins H, Wilde A, Wolpert )] TJ ET
BT 26.250 462.101 Td /F1 9.8 Tf  [(C, Zipes DP. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and )] TJ ET
BT 26.250 450.196 Td /F1 9.8 Tf  [(cardiomyopathies this document was developed as a partnership between the Heart Rhythm Society \(HRS\) and the European )] TJ ET
BT 26.250 438.291 Td /F1 9.8 Tf  [(Heart Rhythm Association \(EHRA\). Heart Rhythm. 2011 Aug;8\(8\):1308-39. PubMed PMID: 21787999.)] TJ ET
BT 26.250 418.887 Td /F1 9.8 Tf  [(7.)] TJ ET
BT 38.132 418.887 Td /F1 9.8 Tf  [(Medeiros-Domingo A, Bhuiyan ZA, Tester DJ, Hofman N, Bikker H, van Tintelen JP, Mannens MM, Wilde AA, Ackerman MJ. )] TJ ET
BT 26.250 406.982 Td /F1 9.8 Tf  [(The RYR2-encoded ryanodine receptor/calcium release channel in patients diagnosed previously with either catecholaminergic )] TJ ET
BT 26.250 395.077 Td /F1 9.8 Tf  [(polymorphic ventricular tachycardia or genotype negative, exercise-induced long QT syndrome: a comprehensive open reading )] TJ ET
BT 26.250 383.172 Td /F1 9.8 Tf  [(frame mutational analysis. J Am Coll Cardiol. 2009 Nov 24;54\(22\):2065-74. PubMed PMID: 19926015; PubMed Central PMCID: )] TJ ET
BT 26.250 371.268 Td /F1 9.8 Tf  [(PMC2880864.)] TJ ET
BT 26.250 351.863 Td /F1 9.8 Tf  [(8.)] TJ ET
BT 38.132 351.863 Td /F1 9.8 Tf  [(Takenaka K, Ai T, Shimizu W, Kobori A, Ninomiya T, Otani H, Kubota T, Takaki H, Kamakura S, Horie M. Exercise stress test )] TJ ET
BT 26.250 339.958 Td /F1 9.8 Tf  [(amplifies genotype-phenotype correlation in the LQT1 and LQT2 forms of the long-QT syndrome. Circulation. 2003 Feb )] TJ ET
BT 26.250 328.053 Td /F1 9.8 Tf  [(18;107\(6\):838-44. PubMed PMID: 12591753.)] TJ ET
BT 26.250 308.649 Td /F1 9.8 Tf  [(9.)] TJ ET
BT 38.132 308.649 Td /F1 9.8 Tf  [(Hofman N, Tan HL, Alders M, van Langen IM, Wilde AA. Active cascade screening in primary inherited arrhythmia )] TJ ET
BT 26.250 296.744 Td /F1 9.8 Tf  [(syndromes: does it lead to prophylactic treatment? J Am Coll Cardiol. 2010 Jun 8;55\(23\):2570-6. PubMed PMID: 20513597.)] TJ ET
BT 26.250 277.339 Td /F1 9.8 Tf  [(10.)] TJ ET
BT 43.553 277.339 Td /F1 9.8 Tf  [(Goldenberg I, Moss AJ, Peterson DR, McNitt S, Zareba W, Andrews ML, Robinson JL, Locati EH, Ackerman MJ, Benhorin )] TJ ET
BT 26.250 265.434 Td /F1 9.8 Tf  [(J, Kaufman ES, Napolitano C, Priori SG, Qi M, Schwartz PJ, Towbin JA, Vincent GM, Zhang L. Risk factors for aborted cardiac )] TJ ET
BT 26.250 253.530 Td /F1 9.8 Tf  [(arrest and sudden cardiac death in children with the congenital long-QT syndrome. Circulation. 2008 Apr 29;117\(17\):2184-91. )] TJ ET
BT 26.250 241.625 Td /F1 9.8 Tf  [(Epub 2008 Apr 21. PubMed PMID: 18427136.)] TJ ET
BT 26.250 222.220 Td /F1 9.8 Tf  [(11.)] TJ ET
BT 43.553 222.220 Td /F1 9.8 Tf  [(Moss AJ, Goldenberg I. Importance of Knowing the Genotype and the Specific Mutation When Managing Patients with Long )] TJ ET
BT 26.250 210.315 Td /F1 9.8 Tf  [(QT Syndrome. Circ Arrhythm Electrophysiol. 2008 Aug;1\(3\):213-26; discussion 226. Review. PubMed PMID: 19701491; )] TJ ET
BT 26.250 198.411 Td /F1 9.8 Tf  [(PubMed Central PMCID: PMC2729934.)] TJ ET
BT 26.250 179.006 Td /F1 9.8 Tf  [(12.)] TJ ET
BT 43.553 179.006 Td /F1 9.8 Tf  [(Hobbs JB, Peterson DR, Moss AJ, McNitt S, Zareba W, Goldenberg I, Qi M, Robinson JL, Sauer AJ, Ackerman MJ, )] TJ ET
BT 26.250 167.101 Td /F1 9.8 Tf  [(Benhorin J, Kaufman ES, Locati EH, Napolitano C, Priori SG, Towbin JA, Vincent GM, Zhang L. Risk of aborted cardiac arrest )] TJ ET
BT 26.250 155.196 Td /F1 9.8 Tf  [(or sudden cardiac death during adolescence in the long-QT syndrome. JAMA. 2006 Sep 13;296\(10\):1249-54. PubMed PMID: )] TJ ET
BT 26.250 143.292 Td /F1 9.8 Tf  [(16968849.)] TJ ET
BT 26.250 123.887 Td /F1 9.8 Tf  [(13.)] TJ ET
BT 43.553 123.887 Td /F1 9.8 Tf  [(Moss AJ, Zareba W, Hall WJ, Schwartz PJ, Crampton RS, Benhorin J, Vincent GM, Locati EH, Priori SG, Napolitano C, )] TJ ET
BT 26.250 111.982 Td /F1 9.8 Tf  [(Medina A, Zhang L, Robinson JL, Timothy K, Towbin JA, Andrews ML. Effectiveness and limitations of beta-blocker therapy in )] TJ ET
BT 26.250 100.077 Td /F1 9.8 Tf  [(congenital long-QT syndrome. Circulation. 2000 Feb 15;101\(6\):616-23. PubMed PMID: 10673253.)] TJ ET
BT 26.250 80.673 Td /F1 9.8 Tf  [(14.)] TJ ET
BT 43.553 80.673 Td /F1 9.8 Tf  [(National Center for Biotechnology Information \(NCBI\). Long QT syndrome 1: clinical laboratories. Available at: )] TJ ET
BT 26.250 68.768 Td /F1 9.8 Tf  [(https://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/clinical_disease_id/115871?db=genetests. Accessed 28 Apr 2011.)] TJ ET
BT 26.250 49.363 Td /F1 9.8 Tf  [(15.)] TJ ET
BT 43.553 49.363 Td /F1 9.8 Tf  [(Tzou WS, Gerstenfeld EP. Genetic testing in the management of inherited arrhythmia syndromes. Curr Cardiol Rep. 2009 )] TJ ET
Q
q
0.000 0.000 0.000 rg
BT 291.710 19.825 Td /F1 11.0 Tf  [(6)] TJ ET
BT 25.000 19.825 Td /F1 11.0 Tf  [(PLOS Currents Evidence on Genomic Tests)] TJ ET

Q
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0.271 0.267 0.267 rg
q
15.000 39.263 577.500 737.737 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F1 9.8 Tf  [(Sep;11\(5\):343-51. Review. PubMed PMID: 19709494.)] TJ ET
BT 26.250 748.071 Td /F1 9.8 Tf  [(16.)] TJ ET
BT 43.553 748.071 Td /F1 9.8 Tf  [(Vincent GM, Zhang L. The role of genotyping in diagnosing cardiac channelopathies : progress to date. Mol Diagn. )] TJ ET
BT 26.250 736.167 Td /F1 9.8 Tf  [(2005;9\(3\):105-18. Review. PubMed PMID: 16271012.)] TJ ET
BT 26.250 716.762 Td /F1 9.8 Tf  [(17.)] TJ ET
BT 43.553 716.762 Td /F1 9.8 Tf  [(Transgenomic. FAMILION technical specifications. Available at: )] TJ ET
BT 26.250 704.857 Td /F1 9.8 Tf  [(https://www.familion.com/familion/pdf/FAMILION%20Tech%20Sheet%20Dec%2011%20482301-06.pdf. Accessed 16 Feb 2012.)] TJ ET
BT 26.250 685.452 Td /F1 9.8 Tf  [(18.)] TJ ET
BT 43.553 685.452 Td /F1 9.8 Tf  [(GeneDx. Cardiology genetics: long QT syndrome \(LQTS\) and short QT \(SQTS\) panels. Available at: )] TJ ET
BT 26.250 673.548 Td /F1 9.8 Tf  [(https://www.genedx.com/ext_upload_files/info_sheet_lqt.pdf and https://www.genedx.com/ext_upload_files/info_sheet_sql.pdf. )] TJ ET
BT 26.250 661.643 Td /F1 9.8 Tf  [(Accessed 16 Feb 2012.)] TJ ET
BT 26.250 642.238 Td /F1 9.8 Tf  [(19.)] TJ ET
BT 43.553 642.238 Td /F1 9.8 Tf  [(Masonic Medical Research Laboratory. Genetic screening. Available at: www.mmrl.edu/GeneticScreening.asp. Accessed )] TJ ET
BT 26.250 630.333 Td /F1 9.8 Tf  [(29 Mar 2011.)] TJ ET
BT 26.250 610.929 Td /F1 9.8 Tf  [(20.)] TJ ET
BT 43.553 610.929 Td /F1 9.8 Tf  [(Lehmann MH, Brugada R. Brugada syndrome: diagnostic pitfalls. J Emerg Med. 2009 Jul;37\(1\):79-81; author reply 81-2. )] TJ ET
BT 26.250 599.024 Td /F1 9.8 Tf  [(Epub 2009 Mar 25. PubMed PMID: 19321285.)] TJ ET
BT 26.250 579.619 Td /F1 9.8 Tf  [(21.)] TJ ET
BT 43.553 579.619 Td /F1 9.8 Tf  [(Modell SM, Lehmann MH. The long QT syndrome family of cardiac ion channelopathies: a HuGE review. Genet Med. 2006 )] TJ ET
BT 26.250 567.714 Td /F1 9.8 Tf  [(Mar;8\(3\):143-55. Review. PubMed PMID: 16540748.)] TJ ET
BT 26.250 548.310 Td /F1 9.8 Tf  [(22.)] TJ ET
BT 43.553 548.310 Td /F1 9.8 Tf  [(Ackerman MJ. Cardiac causes of sudden unexpected death in children and their relationship to seizures and syncope: )] TJ ET
BT 26.250 536.405 Td /F1 9.8 Tf  [(genetic testing for cardiac electropathies. Semin Pediatr Neurol. 2005 Mar;12\(1\):52-8. Review. PubMed PMID: 15929465.)] TJ ET
BT 26.250 517.000 Td /F1 9.8 Tf  [(23.)] TJ ET
BT 43.553 517.000 Td /F1 9.8 Tf  [(Brugada R, Campuzano O, Brugada P, Brugada J, Hong K. Brugada Syndrome . 2005 Mar 31 [updated 2012 Jan 12]. In: )] TJ ET
BT 26.250 505.095 Td /F1 9.8 Tf  [(Pagon RA, Bird TD, Dolan CR, Stephens K, editors. GeneReviews [Internet]. Seattle \(WA\): University of Washington, Seattle; )] TJ ET
BT 26.250 493.191 Td /F1 9.8 Tf  [(1993-. Available from https://www.ncbi.nlm.nih.gov/books/NBK1517/ PubMed PMID: 20301690.)] TJ ET
BT 26.250 473.786 Td /F1 9.8 Tf  [(24.)] TJ ET
BT 43.553 473.786 Td /F1 9.8 Tf  [(van der Werf C, Hofman N, Tan HL, van Dessel PF, Alders M, van der Wal AC, van Langen IM, Wilde AA. Diagnostic yield )] TJ ET
BT 26.250 461.881 Td /F1 9.8 Tf  [(in sudden unexplained death and aborted cardiac arrest in the young: the experience of a tertiary referral center in The )] TJ ET
BT 26.250 449.976 Td /F1 9.8 Tf  [(Netherlands. Heart Rhythm. 2010 Oct;7\(10\):1383-9. Epub 2010 May 31. PubMed PMID: 20646679.)] TJ ET
BT 26.250 430.572 Td /F1 9.8 Tf  [(25.)] TJ ET
BT 43.553 430.572 Td /F1 9.8 Tf  [(Antzelevitch C, Brugada P, Borggrefe M, Brugada J, Brugada R, Corrado D, Gussak I, LeMarec H, Nademanee K, Perez )] TJ ET
BT 26.250 418.667 Td /F1 9.8 Tf  [(Riera AR, Shimizu W, Schulze-Bahr E, Tan H, Wilde A. Brugada syndrome: report of the second consensus conference: )] TJ ET
BT 26.250 406.762 Td /F1 9.8 Tf  [(endorsed by the Heart Rhythm Society and the European Heart Rhythm Association. Circulation. 2005 Feb 8;111\(5\):659-70. )] TJ ET
BT 26.250 394.857 Td /F1 9.8 Tf  [(Epub 2005 Jan 17. Review. Erratum in: Circulation. 2005 Jul 26;112\(4\):e74. PubMed PMID: 15655131.)] TJ ET
BT 26.250 375.453 Td /F1 9.8 Tf  [(26.)] TJ ET
BT 43.553 375.453 Td /F1 9.8 Tf  [(Schwartz PJ, Stramba-Badiale M, Crotti L, Pedrazzini M, Besana A, Bosi G, Gabbarini F, Goulene K, Insolia R, Mannarino )] TJ ET
BT 26.250 363.548 Td /F1 9.8 Tf  [(S, Mosca F, Nespoli L, Rimini A, Rosati E, Salice P, Spazzolini C. Prevalence of the congenital long-QT syndrome. Circulation. )] TJ ET
BT 26.250 351.643 Td /F1 9.8 Tf  [(2009 Nov 3;120\(18\):1761-7. Epub 2009 Oct 19. PubMed PMID: 19841298; PubMed Central PMCID: PMC2784143.)] TJ ET
BT 26.250 332.238 Td /F1 9.8 Tf  [(27.)] TJ ET
BT 43.553 332.238 Td /F1 9.8 Tf  [(Priori SG, Schwartz PJ, Napolitano C, Bloise R, Ronchetti E, Grillo M, Vicentini A, Spazzolini C, Nastoli J, Bottelli G, Folli R, )] TJ ET
BT 26.250 320.334 Td /F1 9.8 Tf  [(Cappelletti D. Risk stratification in the long-QT syndrome. N Engl J Med. 2003 May 8;348\(19\):1866-74. PubMed PMID: )] TJ ET
BT 26.250 308.429 Td /F1 9.8 Tf  [(12736279.)] TJ ET
BT 26.250 289.024 Td /F1 9.8 Tf  [(28.)] TJ ET
BT 43.553 289.024 Td /F1 9.8 Tf  [(Moss AJ, Schwartz PJ, Crampton RS, Tzivoni D, Locati EH, MacCluer J, Hall WJ, Weitkamp L, Vincent GM, Garson A Jr, et )] TJ ET
BT 26.250 277.119 Td /F1 9.8 Tf  [(al. The long QT syndrome. Prospective longitudinal study of 328 families. Circulation. 1991 Sep;84\(3\):1136-44. PubMed PMID: )] TJ ET
BT 26.250 265.215 Td /F1 9.8 Tf  [(1884444.)] TJ ET
BT 26.250 245.810 Td /F1 9.8 Tf  [(29.)] TJ ET
BT 43.553 245.810 Td /F1 9.8 Tf  [(Schimpf R, Wolpert C, Gaita F, Giustetto C, Borggrefe M. Short QT syndrome. Cardiovasc Res. 2005 Aug 15;67\(3\):357-66. )] TJ ET
BT 26.250 233.905 Td /F1 9.8 Tf  [(Review. PubMed PMID: 15890322.)] TJ ET
BT 26.250 214.500 Td /F1 9.8 Tf  [(30.)] TJ ET
BT 43.553 214.500 Td /F1 9.8 Tf  [(Fowler SJ, Napolitano C, Priori SG. When is genetic testing useful in patients suspected to have inherited cardiac )] TJ ET
BT 26.250 202.596 Td /F1 9.8 Tf  [(arrhythmias? Curr Opin Cardiol. 2010 Jan;25\(1\):37-45. Review. PubMed PMID: 19864943.)] TJ ET
BT 26.250 183.191 Td /F1 9.8 Tf  [(31.)] TJ ET
BT 43.553 183.191 Td /F1 9.8 Tf  [(Garratt CJ, Elliott P, Behr E, Camm AJ, Cowan C, Cruickshank S, Grace A, Griffith MJ, Jolly A, Lambiase P, McKeown P, )] TJ ET
BT 26.250 171.286 Td /F1 9.8 Tf  [(O'Callagan P, Stuart G, Watkins H; Heart Rhythm UK Familial Sudden Cardiac Death Syndromes Statement Development )] TJ ET
BT 26.250 159.381 Td /F1 9.8 Tf  [(Group. Heart Rhythm UK position statement on clinical indications for implantable cardioverter defibrillators in adult patients with )] TJ ET
BT 26.250 147.477 Td /F1 9.8 Tf  [(familial sudden cardiac death syndromes. Europace. 2010 Aug;12\(8\):1156-75. PubMed PMID: 20663787.)] TJ ET
BT 26.250 128.072 Td /F1 9.8 Tf  [(32.)] TJ ET
BT 43.553 128.072 Td /F1 9.8 Tf  [(Miyasaka Y, Tsuji H, Yamada K, Tokunaga S, Saito D, Imuro Y, Matsumoto N, Iwasaka T. Prevalence and mortality of the )] TJ ET
BT 26.250 116.167 Td /F1 9.8 Tf  [(Brugada-type electrocardiogram in one city in Japan. J Am Coll Cardiol. 2001 Sep;38\(3\):771-4. PubMed PMID: 11527631.)] TJ ET
BT 26.250 96.762 Td /F1 9.8 Tf  [(33.)] TJ ET
BT 43.553 96.762 Td /F1 9.8 Tf  [(Gallagher MM, Forleo GB, Behr ER, Magliano G, De Luca L, Morgia V, De Liberato F, Romeo F. Prevalence and )] TJ ET
BT 26.250 84.858 Td /F1 9.8 Tf  [(significance of Brugada-type ECG in 12,012 apparently healthy European subjects. Int J Cardiol. 2008 Oct 30;130\(1\):44-8. )] TJ ET
BT 26.250 72.953 Td /F1 9.8 Tf  [(Epub 2007 Dec 4. PubMed PMID: 18054807.)] TJ ET
BT 26.250 53.548 Td /F1 9.8 Tf  [(34.)] TJ ET
BT 43.553 53.548 Td /F1 9.8 Tf  [(Brugada J, Brugada R, Antzelevitch C, Towbin J, Nademanee K, Brugada P. Long-term follow-up of individuals with the )] TJ ET
Q
q
15.000 39.263 577.500 737.737 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F1 9.8 Tf  [(Sep;11\(5\):343-51. Review. PubMed PMID: 19709494.)] TJ ET
BT 26.250 748.071 Td /F1 9.8 Tf  [(16.)] TJ ET
BT 43.553 748.071 Td /F1 9.8 Tf  [(Vincent GM, Zhang L. The role of genotyping in diagnosing cardiac channelopathies : progress to date. Mol Diagn. )] TJ ET
BT 26.250 736.167 Td /F1 9.8 Tf  [(2005;9\(3\):105-18. Review. PubMed PMID: 16271012.)] TJ ET
BT 26.250 716.762 Td /F1 9.8 Tf  [(17.)] TJ ET
BT 43.553 716.762 Td /F1 9.8 Tf  [(Transgenomic. FAMILION technical specifications. Available at: )] TJ ET
BT 26.250 704.857 Td /F1 9.8 Tf  [(https://www.familion.com/familion/pdf/FAMILION%20Tech%20Sheet%20Dec%2011%20482301-06.pdf. Accessed 16 Feb 2012.)] TJ ET
BT 26.250 685.452 Td /F1 9.8 Tf  [(18.)] TJ ET
BT 43.553 685.452 Td /F1 9.8 Tf  [(GeneDx. Cardiology genetics: long QT syndrome \(LQTS\) and short QT \(SQTS\) panels. Available at: )] TJ ET
BT 26.250 673.548 Td /F1 9.8 Tf  [(https://www.genedx.com/ext_upload_files/info_sheet_lqt.pdf and https://www.genedx.com/ext_upload_files/info_sheet_sql.pdf. )] TJ ET
BT 26.250 661.643 Td /F1 9.8 Tf  [(Accessed 16 Feb 2012.)] TJ ET
BT 26.250 642.238 Td /F1 9.8 Tf  [(19.)] TJ ET
BT 43.553 642.238 Td /F1 9.8 Tf  [(Masonic Medical Research Laboratory. Genetic screening. Available at: www.mmrl.edu/GeneticScreening.asp. Accessed )] TJ ET
BT 26.250 630.333 Td /F1 9.8 Tf  [(29 Mar 2011.)] TJ ET
BT 26.250 610.929 Td /F1 9.8 Tf  [(20.)] TJ ET
BT 43.553 610.929 Td /F1 9.8 Tf  [(Lehmann MH, Brugada R. Brugada syndrome: diagnostic pitfalls. J Emerg Med. 2009 Jul;37\(1\):79-81; author reply 81-2. )] TJ ET
BT 26.250 599.024 Td /F1 9.8 Tf  [(Epub 2009 Mar 25. PubMed PMID: 19321285.)] TJ ET
BT 26.250 579.619 Td /F1 9.8 Tf  [(21.)] TJ ET
BT 43.553 579.619 Td /F1 9.8 Tf  [(Modell SM, Lehmann MH. The long QT syndrome family of cardiac ion channelopathies: a HuGE review. Genet Med. 2006 )] TJ ET
BT 26.250 567.714 Td /F1 9.8 Tf  [(Mar;8\(3\):143-55. Review. PubMed PMID: 16540748.)] TJ ET
BT 26.250 548.310 Td /F1 9.8 Tf  [(22.)] TJ ET
BT 43.553 548.310 Td /F1 9.8 Tf  [(Ackerman MJ. Cardiac causes of sudden unexpected death in children and their relationship to seizures and syncope: )] TJ ET
BT 26.250 536.405 Td /F1 9.8 Tf  [(genetic testing for cardiac electropathies. Semin Pediatr Neurol. 2005 Mar;12\(1\):52-8. Review. PubMed PMID: 15929465.)] TJ ET
BT 26.250 517.000 Td /F1 9.8 Tf  [(23.)] TJ ET
BT 43.553 517.000 Td /F1 9.8 Tf  [(Brugada R, Campuzano O, Brugada P, Brugada J, Hong K. Brugada Syndrome . 2005 Mar 31 [updated 2012 Jan 12]. In: )] TJ ET
BT 26.250 505.095 Td /F1 9.8 Tf  [(Pagon RA, Bird TD, Dolan CR, Stephens K, editors. GeneReviews [Internet]. Seattle \(WA\): University of Washington, Seattle; )] TJ ET
BT 26.250 493.191 Td /F1 9.8 Tf  [(1993-. Available from https://www.ncbi.nlm.nih.gov/books/NBK1517/ PubMed PMID: 20301690.)] TJ ET
BT 26.250 473.786 Td /F1 9.8 Tf  [(24.)] TJ ET
BT 43.553 473.786 Td /F1 9.8 Tf  [(van der Werf C, Hofman N, Tan HL, van Dessel PF, Alders M, van der Wal AC, van Langen IM, Wilde AA. Diagnostic yield )] TJ ET
BT 26.250 461.881 Td /F1 9.8 Tf  [(in sudden unexplained death and aborted cardiac arrest in the young: the experience of a tertiary referral center in The )] TJ ET
BT 26.250 449.976 Td /F1 9.8 Tf  [(Netherlands. Heart Rhythm. 2010 Oct;7\(10\):1383-9. Epub 2010 May 31. PubMed PMID: 20646679.)] TJ ET
BT 26.250 430.572 Td /F1 9.8 Tf  [(25.)] TJ ET
BT 43.553 430.572 Td /F1 9.8 Tf  [(Antzelevitch C, Brugada P, Borggrefe M, Brugada J, Brugada R, Corrado D, Gussak I, LeMarec H, Nademanee K, Perez )] TJ ET
BT 26.250 418.667 Td /F1 9.8 Tf  [(Riera AR, Shimizu W, Schulze-Bahr E, Tan H, Wilde A. Brugada syndrome: report of the second consensus conference: )] TJ ET
BT 26.250 406.762 Td /F1 9.8 Tf  [(endorsed by the Heart Rhythm Society and the European Heart Rhythm Association. Circulation. 2005 Feb 8;111\(5\):659-70. )] TJ ET
BT 26.250 394.857 Td /F1 9.8 Tf  [(Epub 2005 Jan 17. Review. Erratum in: Circulation. 2005 Jul 26;112\(4\):e74. PubMed PMID: 15655131.)] TJ ET
BT 26.250 375.453 Td /F1 9.8 Tf  [(26.)] TJ ET
BT 43.553 375.453 Td /F1 9.8 Tf  [(Schwartz PJ, Stramba-Badiale M, Crotti L, Pedrazzini M, Besana A, Bosi G, Gabbarini F, Goulene K, Insolia R, Mannarino )] TJ ET
BT 26.250 363.548 Td /F1 9.8 Tf  [(S, Mosca F, Nespoli L, Rimini A, Rosati E, Salice P, Spazzolini C. Prevalence of the congenital long-QT syndrome. Circulation. )] TJ ET
BT 26.250 351.643 Td /F1 9.8 Tf  [(2009 Nov 3;120\(18\):1761-7. Epub 2009 Oct 19. PubMed PMID: 19841298; PubMed Central PMCID: PMC2784143.)] TJ ET
BT 26.250 332.238 Td /F1 9.8 Tf  [(27.)] TJ ET
BT 43.553 332.238 Td /F1 9.8 Tf  [(Priori SG, Schwartz PJ, Napolitano C, Bloise R, Ronchetti E, Grillo M, Vicentini A, Spazzolini C, Nastoli J, Bottelli G, Folli R, )] TJ ET
BT 26.250 320.334 Td /F1 9.8 Tf  [(Cappelletti D. Risk stratification in the long-QT syndrome. N Engl J Med. 2003 May 8;348\(19\):1866-74. PubMed PMID: )] TJ ET
BT 26.250 308.429 Td /F1 9.8 Tf  [(12736279.)] TJ ET
BT 26.250 289.024 Td /F1 9.8 Tf  [(28.)] TJ ET
BT 43.553 289.024 Td /F1 9.8 Tf  [(Moss AJ, Schwartz PJ, Crampton RS, Tzivoni D, Locati EH, MacCluer J, Hall WJ, Weitkamp L, Vincent GM, Garson A Jr, et )] TJ ET
BT 26.250 277.119 Td /F1 9.8 Tf  [(al. The long QT syndrome. Prospective longitudinal study of 328 families. Circulation. 1991 Sep;84\(3\):1136-44. PubMed PMID: )] TJ ET
BT 26.250 265.215 Td /F1 9.8 Tf  [(1884444.)] TJ ET
BT 26.250 245.810 Td /F1 9.8 Tf  [(29.)] TJ ET
BT 43.553 245.810 Td /F1 9.8 Tf  [(Schimpf R, Wolpert C, Gaita F, Giustetto C, Borggrefe M. Short QT syndrome. Cardiovasc Res. 2005 Aug 15;67\(3\):357-66. )] TJ ET
BT 26.250 233.905 Td /F1 9.8 Tf  [(Review. PubMed PMID: 15890322.)] TJ ET
BT 26.250 214.500 Td /F1 9.8 Tf  [(30.)] TJ ET
BT 43.553 214.500 Td /F1 9.8 Tf  [(Fowler SJ, Napolitano C, Priori SG. When is genetic testing useful in patients suspected to have inherited cardiac )] TJ ET
BT 26.250 202.596 Td /F1 9.8 Tf  [(arrhythmias? Curr Opin Cardiol. 2010 Jan;25\(1\):37-45. Review. PubMed PMID: 19864943.)] TJ ET
BT 26.250 183.191 Td /F1 9.8 Tf  [(31.)] TJ ET
BT 43.553 183.191 Td /F1 9.8 Tf  [(Garratt CJ, Elliott P, Behr E, Camm AJ, Cowan C, Cruickshank S, Grace A, Griffith MJ, Jolly A, Lambiase P, McKeown P, )] TJ ET
BT 26.250 171.286 Td /F1 9.8 Tf  [(O'Callagan P, Stuart G, Watkins H; Heart Rhythm UK Familial Sudden Cardiac Death Syndromes Statement Development )] TJ ET
BT 26.250 159.381 Td /F1 9.8 Tf  [(Group. Heart Rhythm UK position statement on clinical indications for implantable cardioverter defibrillators in adult patients with )] TJ ET
BT 26.250 147.477 Td /F1 9.8 Tf  [(familial sudden cardiac death syndromes. Europace. 2010 Aug;12\(8\):1156-75. PubMed PMID: 20663787.)] TJ ET
BT 26.250 128.072 Td /F1 9.8 Tf  [(32.)] TJ ET
BT 43.553 128.072 Td /F1 9.8 Tf  [(Miyasaka Y, Tsuji H, Yamada K, Tokunaga S, Saito D, Imuro Y, Matsumoto N, Iwasaka T. Prevalence and mortality of the )] TJ ET
BT 26.250 116.167 Td /F1 9.8 Tf  [(Brugada-type electrocardiogram in one city in Japan. J Am Coll Cardiol. 2001 Sep;38\(3\):771-4. PubMed PMID: 11527631.)] TJ ET
BT 26.250 96.762 Td /F1 9.8 Tf  [(33.)] TJ ET
BT 43.553 96.762 Td /F1 9.8 Tf  [(Gallagher MM, Forleo GB, Behr ER, Magliano G, De Luca L, Morgia V, De Liberato F, Romeo F. Prevalence and )] TJ ET
BT 26.250 84.858 Td /F1 9.8 Tf  [(significance of Brugada-type ECG in 12,012 apparently healthy European subjects. Int J Cardiol. 2008 Oct 30;130\(1\):44-8. )] TJ ET
BT 26.250 72.953 Td /F1 9.8 Tf  [(Epub 2007 Dec 4. PubMed PMID: 18054807.)] TJ ET
BT 26.250 53.548 Td /F1 9.8 Tf  [(34.)] TJ ET
BT 43.553 53.548 Td /F1 9.8 Tf  [(Brugada J, Brugada R, Antzelevitch C, Towbin J, Nademanee K, Brugada P. Long-term follow-up of individuals with the )] TJ ET
Q
q
15.000 39.263 577.500 737.737 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F1 9.8 Tf  [(Sep;11\(5\):343-51. Review. PubMed PMID: 19709494.)] TJ ET
BT 26.250 748.071 Td /F1 9.8 Tf  [(16.)] TJ ET
BT 43.553 748.071 Td /F1 9.8 Tf  [(Vincent GM, Zhang L. The role of genotyping in diagnosing cardiac channelopathies : progress to date. Mol Diagn. )] TJ ET
BT 26.250 736.167 Td /F1 9.8 Tf  [(2005;9\(3\):105-18. Review. PubMed PMID: 16271012.)] TJ ET
BT 26.250 716.762 Td /F1 9.8 Tf  [(17.)] TJ ET
BT 43.553 716.762 Td /F1 9.8 Tf  [(Transgenomic. FAMILION technical specifications. Available at: )] TJ ET
BT 26.250 704.857 Td /F1 9.8 Tf  [(https://www.familion.com/familion/pdf/FAMILION%20Tech%20Sheet%20Dec%2011%20482301-06.pdf. Accessed 16 Feb 2012.)] TJ ET
BT 26.250 685.452 Td /F1 9.8 Tf  [(18.)] TJ ET
BT 43.553 685.452 Td /F1 9.8 Tf  [(GeneDx. Cardiology genetics: long QT syndrome \(LQTS\) and short QT \(SQTS\) panels. Available at: )] TJ ET
BT 26.250 673.548 Td /F1 9.8 Tf  [(https://www.genedx.com/ext_upload_files/info_sheet_lqt.pdf and https://www.genedx.com/ext_upload_files/info_sheet_sql.pdf. )] TJ ET
BT 26.250 661.643 Td /F1 9.8 Tf  [(Accessed 16 Feb 2012.)] TJ ET
BT 26.250 642.238 Td /F1 9.8 Tf  [(19.)] TJ ET
BT 43.553 642.238 Td /F1 9.8 Tf  [(Masonic Medical Research Laboratory. Genetic screening. Available at: www.mmrl.edu/GeneticScreening.asp. Accessed )] TJ ET
BT 26.250 630.333 Td /F1 9.8 Tf  [(29 Mar 2011.)] TJ ET
BT 26.250 610.929 Td /F1 9.8 Tf  [(20.)] TJ ET
BT 43.553 610.929 Td /F1 9.8 Tf  [(Lehmann MH, Brugada R. Brugada syndrome: diagnostic pitfalls. J Emerg Med. 2009 Jul;37\(1\):79-81; author reply 81-2. )] TJ ET
BT 26.250 599.024 Td /F1 9.8 Tf  [(Epub 2009 Mar 25. PubMed PMID: 19321285.)] TJ ET
BT 26.250 579.619 Td /F1 9.8 Tf  [(21.)] TJ ET
BT 43.553 579.619 Td /F1 9.8 Tf  [(Modell SM, Lehmann MH. The long QT syndrome family of cardiac ion channelopathies: a HuGE review. Genet Med. 2006 )] TJ ET
BT 26.250 567.714 Td /F1 9.8 Tf  [(Mar;8\(3\):143-55. Review. PubMed PMID: 16540748.)] TJ ET
BT 26.250 548.310 Td /F1 9.8 Tf  [(22.)] TJ ET
BT 43.553 548.310 Td /F1 9.8 Tf  [(Ackerman MJ. Cardiac causes of sudden unexpected death in children and their relationship to seizures and syncope: )] TJ ET
BT 26.250 536.405 Td /F1 9.8 Tf  [(genetic testing for cardiac electropathies. Semin Pediatr Neurol. 2005 Mar;12\(1\):52-8. Review. PubMed PMID: 15929465.)] TJ ET
BT 26.250 517.000 Td /F1 9.8 Tf  [(23.)] TJ ET
BT 43.553 517.000 Td /F1 9.8 Tf  [(Brugada R, Campuzano O, Brugada P, Brugada J, Hong K. Brugada Syndrome . 2005 Mar 31 [updated 2012 Jan 12]. In: )] TJ ET
BT 26.250 505.095 Td /F1 9.8 Tf  [(Pagon RA, Bird TD, Dolan CR, Stephens K, editors. GeneReviews [Internet]. Seattle \(WA\): University of Washington, Seattle; )] TJ ET
BT 26.250 493.191 Td /F1 9.8 Tf  [(1993-. Available from https://www.ncbi.nlm.nih.gov/books/NBK1517/ PubMed PMID: 20301690.)] TJ ET
BT 26.250 473.786 Td /F1 9.8 Tf  [(24.)] TJ ET
BT 43.553 473.786 Td /F1 9.8 Tf  [(van der Werf C, Hofman N, Tan HL, van Dessel PF, Alders M, van der Wal AC, van Langen IM, Wilde AA. Diagnostic yield )] TJ ET
BT 26.250 461.881 Td /F1 9.8 Tf  [(in sudden unexplained death and aborted cardiac arrest in the young: the experience of a tertiary referral center in The )] TJ ET
BT 26.250 449.976 Td /F1 9.8 Tf  [(Netherlands. Heart Rhythm. 2010 Oct;7\(10\):1383-9. Epub 2010 May 31. PubMed PMID: 20646679.)] TJ ET
BT 26.250 430.572 Td /F1 9.8 Tf  [(25.)] TJ ET
BT 43.553 430.572 Td /F1 9.8 Tf  [(Antzelevitch C, Brugada P, Borggrefe M, Brugada J, Brugada R, Corrado D, Gussak I, LeMarec H, Nademanee K, Perez )] TJ ET
BT 26.250 418.667 Td /F1 9.8 Tf  [(Riera AR, Shimizu W, Schulze-Bahr E, Tan H, Wilde A. Brugada syndrome: report of the second consensus conference: )] TJ ET
BT 26.250 406.762 Td /F1 9.8 Tf  [(endorsed by the Heart Rhythm Society and the European Heart Rhythm Association. Circulation. 2005 Feb 8;111\(5\):659-70. )] TJ ET
BT 26.250 394.857 Td /F1 9.8 Tf  [(Epub 2005 Jan 17. Review. Erratum in: Circulation. 2005 Jul 26;112\(4\):e74. PubMed PMID: 15655131.)] TJ ET
BT 26.250 375.453 Td /F1 9.8 Tf  [(26.)] TJ ET
BT 43.553 375.453 Td /F1 9.8 Tf  [(Schwartz PJ, Stramba-Badiale M, Crotti L, Pedrazzini M, Besana A, Bosi G, Gabbarini F, Goulene K, Insolia R, Mannarino )] TJ ET
BT 26.250 363.548 Td /F1 9.8 Tf  [(S, Mosca F, Nespoli L, Rimini A, Rosati E, Salice P, Spazzolini C. Prevalence of the congenital long-QT syndrome. Circulation. )] TJ ET
BT 26.250 351.643 Td /F1 9.8 Tf  [(2009 Nov 3;120\(18\):1761-7. Epub 2009 Oct 19. PubMed PMID: 19841298; PubMed Central PMCID: PMC2784143.)] TJ ET
BT 26.250 332.238 Td /F1 9.8 Tf  [(27.)] TJ ET
BT 43.553 332.238 Td /F1 9.8 Tf  [(Priori SG, Schwartz PJ, Napolitano C, Bloise R, Ronchetti E, Grillo M, Vicentini A, Spazzolini C, Nastoli J, Bottelli G, Folli R, )] TJ ET
BT 26.250 320.334 Td /F1 9.8 Tf  [(Cappelletti D. Risk stratification in the long-QT syndrome. N Engl J Med. 2003 May 8;348\(19\):1866-74. PubMed PMID: )] TJ ET
BT 26.250 308.429 Td /F1 9.8 Tf  [(12736279.)] TJ ET
BT 26.250 289.024 Td /F1 9.8 Tf  [(28.)] TJ ET
BT 43.553 289.024 Td /F1 9.8 Tf  [(Moss AJ, Schwartz PJ, Crampton RS, Tzivoni D, Locati EH, MacCluer J, Hall WJ, Weitkamp L, Vincent GM, Garson A Jr, et )] TJ ET
BT 26.250 277.119 Td /F1 9.8 Tf  [(al. The long QT syndrome. Prospective longitudinal study of 328 families. Circulation. 1991 Sep;84\(3\):1136-44. PubMed PMID: )] TJ ET
BT 26.250 265.215 Td /F1 9.8 Tf  [(1884444.)] TJ ET
BT 26.250 245.810 Td /F1 9.8 Tf  [(29.)] TJ ET
BT 43.553 245.810 Td /F1 9.8 Tf  [(Schimpf R, Wolpert C, Gaita F, Giustetto C, Borggrefe M. Short QT syndrome. Cardiovasc Res. 2005 Aug 15;67\(3\):357-66. )] TJ ET
BT 26.250 233.905 Td /F1 9.8 Tf  [(Review. PubMed PMID: 15890322.)] TJ ET
BT 26.250 214.500 Td /F1 9.8 Tf  [(30.)] TJ ET
BT 43.553 214.500 Td /F1 9.8 Tf  [(Fowler SJ, Napolitano C, Priori SG. When is genetic testing useful in patients suspected to have inherited cardiac )] TJ ET
BT 26.250 202.596 Td /F1 9.8 Tf  [(arrhythmias? Curr Opin Cardiol. 2010 Jan;25\(1\):37-45. Review. PubMed PMID: 19864943.)] TJ ET
BT 26.250 183.191 Td /F1 9.8 Tf  [(31.)] TJ ET
BT 43.553 183.191 Td /F1 9.8 Tf  [(Garratt CJ, Elliott P, Behr E, Camm AJ, Cowan C, Cruickshank S, Grace A, Griffith MJ, Jolly A, Lambiase P, McKeown P, )] TJ ET
BT 26.250 171.286 Td /F1 9.8 Tf  [(O'Callagan P, Stuart G, Watkins H; Heart Rhythm UK Familial Sudden Cardiac Death Syndromes Statement Development )] TJ ET
BT 26.250 159.381 Td /F1 9.8 Tf  [(Group. Heart Rhythm UK position statement on clinical indications for implantable cardioverter defibrillators in adult patients with )] TJ ET
BT 26.250 147.477 Td /F1 9.8 Tf  [(familial sudden cardiac death syndromes. Europace. 2010 Aug;12\(8\):1156-75. PubMed PMID: 20663787.)] TJ ET
BT 26.250 128.072 Td /F1 9.8 Tf  [(32.)] TJ ET
BT 43.553 128.072 Td /F1 9.8 Tf  [(Miyasaka Y, Tsuji H, Yamada K, Tokunaga S, Saito D, Imuro Y, Matsumoto N, Iwasaka T. Prevalence and mortality of the )] TJ ET
BT 26.250 116.167 Td /F1 9.8 Tf  [(Brugada-type electrocardiogram in one city in Japan. J Am Coll Cardiol. 2001 Sep;38\(3\):771-4. PubMed PMID: 11527631.)] TJ ET
BT 26.250 96.762 Td /F1 9.8 Tf  [(33.)] TJ ET
BT 43.553 96.762 Td /F1 9.8 Tf  [(Gallagher MM, Forleo GB, Behr ER, Magliano G, De Luca L, Morgia V, De Liberato F, Romeo F. Prevalence and )] TJ ET
BT 26.250 84.858 Td /F1 9.8 Tf  [(significance of Brugada-type ECG in 12,012 apparently healthy European subjects. Int J Cardiol. 2008 Oct 30;130\(1\):44-8. )] TJ ET
BT 26.250 72.953 Td /F1 9.8 Tf  [(Epub 2007 Dec 4. PubMed PMID: 18054807.)] TJ ET
BT 26.250 53.548 Td /F1 9.8 Tf  [(34.)] TJ ET
BT 43.553 53.548 Td /F1 9.8 Tf  [(Brugada J, Brugada R, Antzelevitch C, Towbin J, Nademanee K, Brugada P. Long-term follow-up of individuals with the )] TJ ET
Q
q
0.000 0.000 0.000 rg
BT 291.710 19.825 Td /F1 11.0 Tf  [(7)] TJ ET
BT 25.000 19.825 Td /F1 11.0 Tf  [(PLOS Currents Evidence on Genomic Tests)] TJ ET

Q
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0.271 0.267 0.267 rg
q
15.000 36.643 577.500 740.357 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F1 9.8 Tf  [(electrocardiographic pattern of right bundle-branch block and ST-segment elevation in precordial leads V1 to V3. Circulation. )] TJ ET
BT 26.250 755.571 Td /F1 9.8 Tf  [(2002 Jan 1;105\(1\):73-8. PubMed PMID: 11772879.)] TJ ET
BT 26.250 736.167 Td /F1 9.8 Tf  [(35.)] TJ ET
BT 43.553 736.167 Td /F1 9.8 Tf  [(Kapplinger JD, Tester DJ, Alders M, Benito B, Berthet M, Brugada J, Brugada P, Fressart V, Guerchicoff A, Harris-Kerr C, )] TJ ET
BT 26.250 724.262 Td /F1 9.8 Tf  [(Kamakura S, Kyndt F, Koopmann TT, Miyamoto Y, Pfeiffer R, Pollevick GD, Probst V, Zumhagen S, Vatta M, Towbin JA, )] TJ ET
BT 26.250 712.357 Td /F1 9.8 Tf  [(Shimizu W, Schulze-Bahr E, Antzelevitch C, Salisbury BA, Guicheney P, Wilde AA, Brugada R, Schott JJ, Ackerman MJ. An )] TJ ET
BT 26.250 700.452 Td /F1 9.8 Tf  [(international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada )] TJ ET
BT 26.250 688.548 Td /F1 9.8 Tf  [(syndrome genetic testing. Heart Rhythm. 2010 Jan;7\(1\):33-46. Epub 2009 Oct 8. PubMed PMID: 20129283; PubMed Central )] TJ ET
BT 26.250 676.643 Td /F1 9.8 Tf  [(PMCID: PMC2822446.)] TJ ET
BT 26.250 657.238 Td /F1 9.8 Tf  [(36.)] TJ ET
BT 43.553 657.238 Td /F1 9.8 Tf  [(Goldenberg I, Moss AJ, Bradley J, Polonsky S, Peterson DR, McNitt S, Zareba W, Andrews ML, Robinson JL, Ackerman )] TJ ET
BT 26.250 645.333 Td /F1 9.8 Tf  [(MJ, Benhorin J, Kaufman ES, Locati EH, Napolitano C, Priori SG, Qi M, Schwartz PJ, Towbin JA, Vincent GM, Zhang L. Long-)] TJ ET
BT 26.250 633.429 Td /F1 9.8 Tf  [(QT syndrome after age 40. Circulation. 2008 Apr 29;117\(17\):2192-201. Epub 2008 Apr 21. PubMed PMID: 18427134.)] TJ ET
BT 26.250 614.024 Td /F1 9.8 Tf  [(37.)] TJ ET
BT 43.553 614.024 Td /F1 9.8 Tf  [(Tester DJ, Will ML, Haglund CM, Ackerman MJ. Compendium of cardiac channel mutations in 541 consecutive unrelated )] TJ ET
BT 26.250 602.119 Td /F1 9.8 Tf  [(patients referred for long QT syndrome genetic testing. Heart Rhythm. 2005 May;2\(5\):507-17. PubMed PMID: 15840476.)] TJ ET
BT 26.250 582.714 Td /F1 9.8 Tf  [(38.)] TJ ET
BT 43.553 582.714 Td /F1 9.8 Tf  [(Liu JF, Jons C, Moss AJ, McNitt S, Peterson DR, Qi M, Zareba W, Robinson JL, Barsheshet A, Ackerman MJ, Benhorin J, )] TJ ET
BT 26.250 570.810 Td /F1 9.8 Tf  [(Kaufman ES, Locati EH, Napolitano C, Priori SG, Schwartz PJ, Towbin J, Vincent M, Zhang L, Goldenberg I; International Long )] TJ ET
BT 26.250 558.905 Td /F1 9.8 Tf  [(QT Syndrome Registry. Risk Factors for Recurrent Syncope and Subsequent Fatal or Near-Fatal Events in Children and )] TJ ET
BT 26.250 547.000 Td /F1 9.8 Tf  [(Adolescents With Long QT Syndrome. J Am Coll Cardiol. 2011 Feb 22;57\(8\):941-50. Erratum in: J Am Coll Cardiol. 2011 Apr )] TJ ET
BT 26.250 535.095 Td /F1 9.8 Tf  [(19;57\(16\):1717. PubMed PMID: 21329841; PubMed Central PMCID: PMC3052409.)] TJ ET
BT 26.250 515.691 Td /F1 9.8 Tf  [(39.)] TJ ET
BT 43.553 515.691 Td /F1 9.8 Tf  [(Hayes, Inc. Genetic test evaluation reports: Genetic testing for long QT syndrome using the Familion� test )] TJ ET
BT 26.250 503.786 Td /F1 9.8 Tf  [(\(PGxHealthTM\)\(2009\), catecholaminergic polymorphic ventricular tachycardia \(2010\), and Brugada syndrome \(2010\). Lansdale, )] TJ ET
BT 26.250 491.881 Td /F1 9.8 Tf  [(PA: Hayes, Inc. Available at: https://www.hayesinc.com/hayes/products_and_services/knowledge-center. Accessed 4 Apr 2011.)] TJ ET
BT 26.250 472.476 Td /F1 9.8 Tf  [(40.)] TJ ET
BT 43.553 472.476 Td /F1 9.8 Tf  [(DNA Direct, Genomic Medicine Institute. Genetic testing for long QT syndrome. \(systematic reviews\) San Francisco, CA: )] TJ ET
BT 26.250 460.572 Td /F1 9.8 Tf  [(DNA Direct. 2008. Available at: https://www.dnadirect.com/dnaweb/products/policy-benefit-support.html. Accessed 14 Apr 2011.)] TJ ET
BT 26.250 441.167 Td /F1 9.8 Tf  [(41.)] TJ ET
BT 43.553 441.167 Td /F1 9.8 Tf  [(Blue Cross Blue Shield Association \(BCBSA\), Technology Evaluation Center \(TEC\). Genetic testing for long QT syndrome. )] TJ ET
BT 26.250 429.262 Td /F1 9.8 Tf  [(2007 TEC Assessments 2008;22\(9\). Chicago, IL. Available at: https://www.sads.org/images/stories/bcbstecadvisory.pdf. )] TJ ET
BT 26.250 417.357 Td /F1 9.8 Tf  [(Accessed 10 Dec 2010.)] TJ ET
BT 26.250 397.953 Td /F1 9.8 Tf  [(42.)] TJ ET
BT 43.553 397.953 Td /F1 9.8 Tf  [(Australia and New Zealand Horizon Scanning Network \(ANZHSN\). Horizon scanning technology horizon scanning report: )] TJ ET
BT 26.250 386.048 Td /F1 9.8 Tf  [(genetic testing for congenital long QT syndrome. Canberra, Australia: Australian Government Department of Health and Ageing. )] TJ ET
BT 26.250 374.143 Td /F1 9.8 Tf  [(May 2007. Available at: )] TJ ET
BT 26.250 362.238 Td /F1 9.8 Tf  [(https://www.horizonscanning.gov.au/internet/horizon/publishing.nsf/Content/58685F8B48CC9EE7CA2575AD0080F340/$File/Final_Long_QT_HS_Report.pdf. )] TJ ET
BT 26.250 350.334 Td /F1 9.8 Tf  [(Accessed Dec 10, 2010.)] TJ ET
BT 26.250 330.929 Td /F1 9.8 Tf  [(43.)] TJ ET
BT 43.553 330.929 Td /F1 9.8 Tf  [(Brugada R, Campuzano O, Brugada P, Brugada J, Hong K. Brugada Syndrome . 2005 Mar 31 [updated 2012 Jan 12]. In: )] TJ ET
BT 26.250 319.024 Td /F1 9.8 Tf  [(Pagon RA, Bird TD, Dolan CR, Stephens K, editors. GeneReviews [Internet]. Seattle \(WA\): University of Washington, Seattle; )] TJ ET
BT 26.250 307.119 Td /F1 9.8 Tf  [(1993-. Available from https://www.ncbi.nlm.nih.gov/books/NBK1517/ PubMed PMID: 20301690.)] TJ ET
BT 26.250 287.715 Td /F1 9.8 Tf  [(44.)] TJ ET
BT 43.553 287.715 Td /F1 9.8 Tf  [(Priori SG, Napolitano C. Role of genetic analyses in cardiology: part I: mendelian diseases: cardiac channelopathies. )] TJ ET
BT 26.250 275.810 Td /F1 9.8 Tf  [(Circulation. 2006 Feb 28;113\(8\):1130-5. Review. PubMed PMID: 16505190.)] TJ ET
BT 26.250 256.405 Td /F1 9.8 Tf  [(45.)] TJ ET
BT 43.553 256.405 Td /F1 9.8 Tf  [(Lehnart SE, Ackerman MJ, Benson DW Jr, Brugada R, Clancy CE, Donahue JK, George AL Jr, Grant AO, Groft SC, )] TJ ET
BT 26.250 244.500 Td /F1 9.8 Tf  [(January CT, Lathrop DA, Lederer WJ, Makielski JC, Mohler PJ, Moss A, Nerbonne JM, Olson TM, Przywara DA, Towbin JA, )] TJ ET
BT 26.250 232.596 Td /F1 9.8 Tf  [(Wang LH, Marks AR. Inherited arrhythmias: a National Heart, Lung, and Blood Institute and Office of Rare Diseases workshop )] TJ ET
BT 26.250 220.691 Td /F1 9.8 Tf  [(consensus report about the diagnosis, phenotyping, molecular mechanisms, and therapeutic approaches for primary )] TJ ET
BT 26.250 208.786 Td /F1 9.8 Tf  [(cardiomyopathies of gene mutations affecting ion channel function. Circulation. 2007 Nov 13;116\(20\):2325-45. Erratum in: )] TJ ET
BT 26.250 196.881 Td /F1 9.8 Tf  [(Circulation. 2008 Aug 19;118\(8\):e132. PubMed PMID: 17998470.)] TJ ET
BT 26.250 177.477 Td /F1 9.8 Tf  [(46.)] TJ ET
BT 43.553 177.477 Td /F1 9.8 Tf  [(Garratt CJ, Elliott P, Behr E, Camm AJ, Cowan C, Cruickshank S, Grace A, Griffith MJ, Jolly A, Lambiase P, McKeown P, )] TJ ET
BT 26.250 165.572 Td /F1 9.8 Tf  [(O'Callagan P, Stuart G, Watkins H; Heart Rhythm UK Familial Sudden Cardiac Death Syndromes Statement Development )] TJ ET
BT 26.250 153.667 Td /F1 9.8 Tf  [(Group. Heart Rhythm UK position statement on clinical indications for implantable cardioverter defibrillators in adult patients with )] TJ ET
BT 26.250 141.762 Td /F1 9.8 Tf  [(familial sudden cardiac death syndromes. Europace. 2010 Aug;12\(8\):1156-75. PubMed PMID: 20663787.)] TJ ET
BT 26.250 122.358 Td /F1 9.8 Tf  [(47.)] TJ ET
BT 43.553 122.358 Td /F1 9.8 Tf  [(Zipes DP, Camm AJ, Borggrefe M, Buxton AE, Chaitman B, Fromer M, Gregoratos G, Klein G, Moss AJ, Myerburg RJ, )] TJ ET
BT 26.250 110.453 Td /F1 9.8 Tf  [(Priori SG, Quinones MA, Roden DM, Silka MJ, Tracy C, Smith SC Jr, Jacobs AK, Adams CD, Antman EM, Anderson JL, Hunt )] TJ ET
BT 26.250 98.548 Td /F1 9.8 Tf  [(SA, Halperin JL, Nishimura R, Ornato JP, Page RL, Riegel B, Blanc JJ, Budaj A, Dean V, Deckers JW, Despres C, Dickstein K, )] TJ ET
BT 26.250 86.643 Td /F1 9.8 Tf  [(Lekakis J, McGregor K, Metra M, Morais J, Osterspey A, Tamargo JL, Zamorano JL; American College of Cardiology/American )] TJ ET
BT 26.250 74.739 Td /F1 9.8 Tf  [(Heart Association Task Force; European Society of Cardiology Committee for Practice Guidelines; European Heart Rhythm )] TJ ET
BT 26.250 62.834 Td /F1 9.8 Tf  [(Association; Heart Rhythm Society. ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias )] TJ ET
BT 26.250 50.929 Td /F1 9.8 Tf  [(and the Prevention of Sudden Cardiac Death: a report of the American College of Cardiology/American Heart Association Task )] TJ ET
Q
q
15.000 36.643 577.500 740.357 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F1 9.8 Tf  [(electrocardiographic pattern of right bundle-branch block and ST-segment elevation in precordial leads V1 to V3. Circulation. )] TJ ET
BT 26.250 755.571 Td /F1 9.8 Tf  [(2002 Jan 1;105\(1\):73-8. PubMed PMID: 11772879.)] TJ ET
BT 26.250 736.167 Td /F1 9.8 Tf  [(35.)] TJ ET
BT 43.553 736.167 Td /F1 9.8 Tf  [(Kapplinger JD, Tester DJ, Alders M, Benito B, Berthet M, Brugada J, Brugada P, Fressart V, Guerchicoff A, Harris-Kerr C, )] TJ ET
BT 26.250 724.262 Td /F1 9.8 Tf  [(Kamakura S, Kyndt F, Koopmann TT, Miyamoto Y, Pfeiffer R, Pollevick GD, Probst V, Zumhagen S, Vatta M, Towbin JA, )] TJ ET
BT 26.250 712.357 Td /F1 9.8 Tf  [(Shimizu W, Schulze-Bahr E, Antzelevitch C, Salisbury BA, Guicheney P, Wilde AA, Brugada R, Schott JJ, Ackerman MJ. An )] TJ ET
BT 26.250 700.452 Td /F1 9.8 Tf  [(international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada )] TJ ET
BT 26.250 688.548 Td /F1 9.8 Tf  [(syndrome genetic testing. Heart Rhythm. 2010 Jan;7\(1\):33-46. Epub 2009 Oct 8. PubMed PMID: 20129283; PubMed Central )] TJ ET
BT 26.250 676.643 Td /F1 9.8 Tf  [(PMCID: PMC2822446.)] TJ ET
BT 26.250 657.238 Td /F1 9.8 Tf  [(36.)] TJ ET
BT 43.553 657.238 Td /F1 9.8 Tf  [(Goldenberg I, Moss AJ, Bradley J, Polonsky S, Peterson DR, McNitt S, Zareba W, Andrews ML, Robinson JL, Ackerman )] TJ ET
BT 26.250 645.333 Td /F1 9.8 Tf  [(MJ, Benhorin J, Kaufman ES, Locati EH, Napolitano C, Priori SG, Qi M, Schwartz PJ, Towbin JA, Vincent GM, Zhang L. Long-)] TJ ET
BT 26.250 633.429 Td /F1 9.8 Tf  [(QT syndrome after age 40. Circulation. 2008 Apr 29;117\(17\):2192-201. Epub 2008 Apr 21. PubMed PMID: 18427134.)] TJ ET
BT 26.250 614.024 Td /F1 9.8 Tf  [(37.)] TJ ET
BT 43.553 614.024 Td /F1 9.8 Tf  [(Tester DJ, Will ML, Haglund CM, Ackerman MJ. Compendium of cardiac channel mutations in 541 consecutive unrelated )] TJ ET
BT 26.250 602.119 Td /F1 9.8 Tf  [(patients referred for long QT syndrome genetic testing. Heart Rhythm. 2005 May;2\(5\):507-17. PubMed PMID: 15840476.)] TJ ET
BT 26.250 582.714 Td /F1 9.8 Tf  [(38.)] TJ ET
BT 43.553 582.714 Td /F1 9.8 Tf  [(Liu JF, Jons C, Moss AJ, McNitt S, Peterson DR, Qi M, Zareba W, Robinson JL, Barsheshet A, Ackerman MJ, Benhorin J, )] TJ ET
BT 26.250 570.810 Td /F1 9.8 Tf  [(Kaufman ES, Locati EH, Napolitano C, Priori SG, Schwartz PJ, Towbin J, Vincent M, Zhang L, Goldenberg I; International Long )] TJ ET
BT 26.250 558.905 Td /F1 9.8 Tf  [(QT Syndrome Registry. Risk Factors for Recurrent Syncope and Subsequent Fatal or Near-Fatal Events in Children and )] TJ ET
BT 26.250 547.000 Td /F1 9.8 Tf  [(Adolescents With Long QT Syndrome. J Am Coll Cardiol. 2011 Feb 22;57\(8\):941-50. Erratum in: J Am Coll Cardiol. 2011 Apr )] TJ ET
BT 26.250 535.095 Td /F1 9.8 Tf  [(19;57\(16\):1717. PubMed PMID: 21329841; PubMed Central PMCID: PMC3052409.)] TJ ET
BT 26.250 515.691 Td /F1 9.8 Tf  [(39.)] TJ ET
BT 43.553 515.691 Td /F1 9.8 Tf  [(Hayes, Inc. Genetic test evaluation reports: Genetic testing for long QT syndrome using the Familion� test )] TJ ET
BT 26.250 503.786 Td /F1 9.8 Tf  [(\(PGxHealthTM\)\(2009\), catecholaminergic polymorphic ventricular tachycardia \(2010\), and Brugada syndrome \(2010\). Lansdale, )] TJ ET
BT 26.250 491.881 Td /F1 9.8 Tf  [(PA: Hayes, Inc. Available at: https://www.hayesinc.com/hayes/products_and_services/knowledge-center. Accessed 4 Apr 2011.)] TJ ET
BT 26.250 472.476 Td /F1 9.8 Tf  [(40.)] TJ ET
BT 43.553 472.476 Td /F1 9.8 Tf  [(DNA Direct, Genomic Medicine Institute. Genetic testing for long QT syndrome. \(systematic reviews\) San Francisco, CA: )] TJ ET
BT 26.250 460.572 Td /F1 9.8 Tf  [(DNA Direct. 2008. Available at: https://www.dnadirect.com/dnaweb/products/policy-benefit-support.html. Accessed 14 Apr 2011.)] TJ ET
BT 26.250 441.167 Td /F1 9.8 Tf  [(41.)] TJ ET
BT 43.553 441.167 Td /F1 9.8 Tf  [(Blue Cross Blue Shield Association \(BCBSA\), Technology Evaluation Center \(TEC\). Genetic testing for long QT syndrome. )] TJ ET
BT 26.250 429.262 Td /F1 9.8 Tf  [(2007 TEC Assessments 2008;22\(9\). Chicago, IL. Available at: https://www.sads.org/images/stories/bcbstecadvisory.pdf. )] TJ ET
BT 26.250 417.357 Td /F1 9.8 Tf  [(Accessed 10 Dec 2010.)] TJ ET
BT 26.250 397.953 Td /F1 9.8 Tf  [(42.)] TJ ET
BT 43.553 397.953 Td /F1 9.8 Tf  [(Australia and New Zealand Horizon Scanning Network \(ANZHSN\). Horizon scanning technology horizon scanning report: )] TJ ET
BT 26.250 386.048 Td /F1 9.8 Tf  [(genetic testing for congenital long QT syndrome. Canberra, Australia: Australian Government Department of Health and Ageing. )] TJ ET
BT 26.250 374.143 Td /F1 9.8 Tf  [(May 2007. Available at: )] TJ ET
BT 26.250 362.238 Td /F1 9.8 Tf  [(https://www.horizonscanning.gov.au/internet/horizon/publishing.nsf/Content/58685F8B48CC9EE7CA2575AD0080F340/$File/Final_Long_QT_HS_Report.pdf. )] TJ ET
BT 26.250 350.334 Td /F1 9.8 Tf  [(Accessed Dec 10, 2010.)] TJ ET
BT 26.250 330.929 Td /F1 9.8 Tf  [(43.)] TJ ET
BT 43.553 330.929 Td /F1 9.8 Tf  [(Brugada R, Campuzano O, Brugada P, Brugada J, Hong K. Brugada Syndrome . 2005 Mar 31 [updated 2012 Jan 12]. In: )] TJ ET
BT 26.250 319.024 Td /F1 9.8 Tf  [(Pagon RA, Bird TD, Dolan CR, Stephens K, editors. GeneReviews [Internet]. Seattle \(WA\): University of Washington, Seattle; )] TJ ET
BT 26.250 307.119 Td /F1 9.8 Tf  [(1993-. Available from https://www.ncbi.nlm.nih.gov/books/NBK1517/ PubMed PMID: 20301690.)] TJ ET
BT 26.250 287.715 Td /F1 9.8 Tf  [(44.)] TJ ET
BT 43.553 287.715 Td /F1 9.8 Tf  [(Priori SG, Napolitano C. Role of genetic analyses in cardiology: part I: mendelian diseases: cardiac channelopathies. )] TJ ET
BT 26.250 275.810 Td /F1 9.8 Tf  [(Circulation. 2006 Feb 28;113\(8\):1130-5. Review. PubMed PMID: 16505190.)] TJ ET
BT 26.250 256.405 Td /F1 9.8 Tf  [(45.)] TJ ET
BT 43.553 256.405 Td /F1 9.8 Tf  [(Lehnart SE, Ackerman MJ, Benson DW Jr, Brugada R, Clancy CE, Donahue JK, George AL Jr, Grant AO, Groft SC, )] TJ ET
BT 26.250 244.500 Td /F1 9.8 Tf  [(January CT, Lathrop DA, Lederer WJ, Makielski JC, Mohler PJ, Moss A, Nerbonne JM, Olson TM, Przywara DA, Towbin JA, )] TJ ET
BT 26.250 232.596 Td /F1 9.8 Tf  [(Wang LH, Marks AR. Inherited arrhythmias: a National Heart, Lung, and Blood Institute and Office of Rare Diseases workshop )] TJ ET
BT 26.250 220.691 Td /F1 9.8 Tf  [(consensus report about the diagnosis, phenotyping, molecular mechanisms, and therapeutic approaches for primary )] TJ ET
BT 26.250 208.786 Td /F1 9.8 Tf  [(cardiomyopathies of gene mutations affecting ion channel function. Circulation. 2007 Nov 13;116\(20\):2325-45. Erratum in: )] TJ ET
BT 26.250 196.881 Td /F1 9.8 Tf  [(Circulation. 2008 Aug 19;118\(8\):e132. PubMed PMID: 17998470.)] TJ ET
BT 26.250 177.477 Td /F1 9.8 Tf  [(46.)] TJ ET
BT 43.553 177.477 Td /F1 9.8 Tf  [(Garratt CJ, Elliott P, Behr E, Camm AJ, Cowan C, Cruickshank S, Grace A, Griffith MJ, Jolly A, Lambiase P, McKeown P, )] TJ ET
BT 26.250 165.572 Td /F1 9.8 Tf  [(O'Callagan P, Stuart G, Watkins H; Heart Rhythm UK Familial Sudden Cardiac Death Syndromes Statement Development )] TJ ET
BT 26.250 153.667 Td /F1 9.8 Tf  [(Group. Heart Rhythm UK position statement on clinical indications for implantable cardioverter defibrillators in adult patients with )] TJ ET
BT 26.250 141.762 Td /F1 9.8 Tf  [(familial sudden cardiac death syndromes. Europace. 2010 Aug;12\(8\):1156-75. PubMed PMID: 20663787.)] TJ ET
BT 26.250 122.358 Td /F1 9.8 Tf  [(47.)] TJ ET
BT 43.553 122.358 Td /F1 9.8 Tf  [(Zipes DP, Camm AJ, Borggrefe M, Buxton AE, Chaitman B, Fromer M, Gregoratos G, Klein G, Moss AJ, Myerburg RJ, )] TJ ET
BT 26.250 110.453 Td /F1 9.8 Tf  [(Priori SG, Quinones MA, Roden DM, Silka MJ, Tracy C, Smith SC Jr, Jacobs AK, Adams CD, Antman EM, Anderson JL, Hunt )] TJ ET
BT 26.250 98.548 Td /F1 9.8 Tf  [(SA, Halperin JL, Nishimura R, Ornato JP, Page RL, Riegel B, Blanc JJ, Budaj A, Dean V, Deckers JW, Despres C, Dickstein K, )] TJ ET
BT 26.250 86.643 Td /F1 9.8 Tf  [(Lekakis J, McGregor K, Metra M, Morais J, Osterspey A, Tamargo JL, Zamorano JL; American College of Cardiology/American )] TJ ET
BT 26.250 74.739 Td /F1 9.8 Tf  [(Heart Association Task Force; European Society of Cardiology Committee for Practice Guidelines; European Heart Rhythm )] TJ ET
BT 26.250 62.834 Td /F1 9.8 Tf  [(Association; Heart Rhythm Society. ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias )] TJ ET
BT 26.250 50.929 Td /F1 9.8 Tf  [(and the Prevention of Sudden Cardiac Death: a report of the American College of Cardiology/American Heart Association Task )] TJ ET
Q
q
15.000 36.643 577.500 740.357 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F1 9.8 Tf  [(electrocardiographic pattern of right bundle-branch block and ST-segment elevation in precordial leads V1 to V3. Circulation. )] TJ ET
BT 26.250 755.571 Td /F1 9.8 Tf  [(2002 Jan 1;105\(1\):73-8. PubMed PMID: 11772879.)] TJ ET
BT 26.250 736.167 Td /F1 9.8 Tf  [(35.)] TJ ET
BT 43.553 736.167 Td /F1 9.8 Tf  [(Kapplinger JD, Tester DJ, Alders M, Benito B, Berthet M, Brugada J, Brugada P, Fressart V, Guerchicoff A, Harris-Kerr C, )] TJ ET
BT 26.250 724.262 Td /F1 9.8 Tf  [(Kamakura S, Kyndt F, Koopmann TT, Miyamoto Y, Pfeiffer R, Pollevick GD, Probst V, Zumhagen S, Vatta M, Towbin JA, )] TJ ET
BT 26.250 712.357 Td /F1 9.8 Tf  [(Shimizu W, Schulze-Bahr E, Antzelevitch C, Salisbury BA, Guicheney P, Wilde AA, Brugada R, Schott JJ, Ackerman MJ. An )] TJ ET
BT 26.250 700.452 Td /F1 9.8 Tf  [(international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada )] TJ ET
BT 26.250 688.548 Td /F1 9.8 Tf  [(syndrome genetic testing. Heart Rhythm. 2010 Jan;7\(1\):33-46. Epub 2009 Oct 8. PubMed PMID: 20129283; PubMed Central )] TJ ET
BT 26.250 676.643 Td /F1 9.8 Tf  [(PMCID: PMC2822446.)] TJ ET
BT 26.250 657.238 Td /F1 9.8 Tf  [(36.)] TJ ET
BT 43.553 657.238 Td /F1 9.8 Tf  [(Goldenberg I, Moss AJ, Bradley J, Polonsky S, Peterson DR, McNitt S, Zareba W, Andrews ML, Robinson JL, Ackerman )] TJ ET
BT 26.250 645.333 Td /F1 9.8 Tf  [(MJ, Benhorin J, Kaufman ES, Locati EH, Napolitano C, Priori SG, Qi M, Schwartz PJ, Towbin JA, Vincent GM, Zhang L. Long-)] TJ ET
BT 26.250 633.429 Td /F1 9.8 Tf  [(QT syndrome after age 40. Circulation. 2008 Apr 29;117\(17\):2192-201. Epub 2008 Apr 21. PubMed PMID: 18427134.)] TJ ET
BT 26.250 614.024 Td /F1 9.8 Tf  [(37.)] TJ ET
BT 43.553 614.024 Td /F1 9.8 Tf  [(Tester DJ, Will ML, Haglund CM, Ackerman MJ. Compendium of cardiac channel mutations in 541 consecutive unrelated )] TJ ET
BT 26.250 602.119 Td /F1 9.8 Tf  [(patients referred for long QT syndrome genetic testing. Heart Rhythm. 2005 May;2\(5\):507-17. PubMed PMID: 15840476.)] TJ ET
BT 26.250 582.714 Td /F1 9.8 Tf  [(38.)] TJ ET
BT 43.553 582.714 Td /F1 9.8 Tf  [(Liu JF, Jons C, Moss AJ, McNitt S, Peterson DR, Qi M, Zareba W, Robinson JL, Barsheshet A, Ackerman MJ, Benhorin J, )] TJ ET
BT 26.250 570.810 Td /F1 9.8 Tf  [(Kaufman ES, Locati EH, Napolitano C, Priori SG, Schwartz PJ, Towbin J, Vincent M, Zhang L, Goldenberg I; International Long )] TJ ET
BT 26.250 558.905 Td /F1 9.8 Tf  [(QT Syndrome Registry. Risk Factors for Recurrent Syncope and Subsequent Fatal or Near-Fatal Events in Children and )] TJ ET
BT 26.250 547.000 Td /F1 9.8 Tf  [(Adolescents With Long QT Syndrome. J Am Coll Cardiol. 2011 Feb 22;57\(8\):941-50. Erratum in: J Am Coll Cardiol. 2011 Apr )] TJ ET
BT 26.250 535.095 Td /F1 9.8 Tf  [(19;57\(16\):1717. PubMed PMID: 21329841; PubMed Central PMCID: PMC3052409.)] TJ ET
BT 26.250 515.691 Td /F1 9.8 Tf  [(39.)] TJ ET
BT 43.553 515.691 Td /F1 9.8 Tf  [(Hayes, Inc. Genetic test evaluation reports: Genetic testing for long QT syndrome using the Familion� test )] TJ ET
BT 26.250 503.786 Td /F1 9.8 Tf  [(\(PGxHealthTM\)\(2009\), catecholaminergic polymorphic ventricular tachycardia \(2010\), and Brugada syndrome \(2010\). Lansdale, )] TJ ET
BT 26.250 491.881 Td /F1 9.8 Tf  [(PA: Hayes, Inc. Available at: https://www.hayesinc.com/hayes/products_and_services/knowledge-center. Accessed 4 Apr 2011.)] TJ ET
BT 26.250 472.476 Td /F1 9.8 Tf  [(40.)] TJ ET
BT 43.553 472.476 Td /F1 9.8 Tf  [(DNA Direct, Genomic Medicine Institute. Genetic testing for long QT syndrome. \(systematic reviews\) San Francisco, CA: )] TJ ET
BT 26.250 460.572 Td /F1 9.8 Tf  [(DNA Direct. 2008. Available at: https://www.dnadirect.com/dnaweb/products/policy-benefit-support.html. Accessed 14 Apr 2011.)] TJ ET
BT 26.250 441.167 Td /F1 9.8 Tf  [(41.)] TJ ET
BT 43.553 441.167 Td /F1 9.8 Tf  [(Blue Cross Blue Shield Association \(BCBSA\), Technology Evaluation Center \(TEC\). Genetic testing for long QT syndrome. )] TJ ET
BT 26.250 429.262 Td /F1 9.8 Tf  [(2007 TEC Assessments 2008;22\(9\). Chicago, IL. Available at: https://www.sads.org/images/stories/bcbstecadvisory.pdf. )] TJ ET
BT 26.250 417.357 Td /F1 9.8 Tf  [(Accessed 10 Dec 2010.)] TJ ET
BT 26.250 397.953 Td /F1 9.8 Tf  [(42.)] TJ ET
BT 43.553 397.953 Td /F1 9.8 Tf  [(Australia and New Zealand Horizon Scanning Network \(ANZHSN\). Horizon scanning technology horizon scanning report: )] TJ ET
BT 26.250 386.048 Td /F1 9.8 Tf  [(genetic testing for congenital long QT syndrome. Canberra, Australia: Australian Government Department of Health and Ageing. )] TJ ET
BT 26.250 374.143 Td /F1 9.8 Tf  [(May 2007. Available at: )] TJ ET
BT 26.250 362.238 Td /F1 9.8 Tf  [(https://www.horizonscanning.gov.au/internet/horizon/publishing.nsf/Content/58685F8B48CC9EE7CA2575AD0080F340/$File/Final_Long_QT_HS_Report.pdf. )] TJ ET
BT 26.250 350.334 Td /F1 9.8 Tf  [(Accessed Dec 10, 2010.)] TJ ET
BT 26.250 330.929 Td /F1 9.8 Tf  [(43.)] TJ ET
BT 43.553 330.929 Td /F1 9.8 Tf  [(Brugada R, Campuzano O, Brugada P, Brugada J, Hong K. Brugada Syndrome . 2005 Mar 31 [updated 2012 Jan 12]. In: )] TJ ET
BT 26.250 319.024 Td /F1 9.8 Tf  [(Pagon RA, Bird TD, Dolan CR, Stephens K, editors. GeneReviews [Internet]. Seattle \(WA\): University of Washington, Seattle; )] TJ ET
BT 26.250 307.119 Td /F1 9.8 Tf  [(1993-. Available from https://www.ncbi.nlm.nih.gov/books/NBK1517/ PubMed PMID: 20301690.)] TJ ET
BT 26.250 287.715 Td /F1 9.8 Tf  [(44.)] TJ ET
BT 43.553 287.715 Td /F1 9.8 Tf  [(Priori SG, Napolitano C. Role of genetic analyses in cardiology: part I: mendelian diseases: cardiac channelopathies. )] TJ ET
BT 26.250 275.810 Td /F1 9.8 Tf  [(Circulation. 2006 Feb 28;113\(8\):1130-5. Review. PubMed PMID: 16505190.)] TJ ET
BT 26.250 256.405 Td /F1 9.8 Tf  [(45.)] TJ ET
BT 43.553 256.405 Td /F1 9.8 Tf  [(Lehnart SE, Ackerman MJ, Benson DW Jr, Brugada R, Clancy CE, Donahue JK, George AL Jr, Grant AO, Groft SC, )] TJ ET
BT 26.250 244.500 Td /F1 9.8 Tf  [(January CT, Lathrop DA, Lederer WJ, Makielski JC, Mohler PJ, Moss A, Nerbonne JM, Olson TM, Przywara DA, Towbin JA, )] TJ ET
BT 26.250 232.596 Td /F1 9.8 Tf  [(Wang LH, Marks AR. Inherited arrhythmias: a National Heart, Lung, and Blood Institute and Office of Rare Diseases workshop )] TJ ET
BT 26.250 220.691 Td /F1 9.8 Tf  [(consensus report about the diagnosis, phenotyping, molecular mechanisms, and therapeutic approaches for primary )] TJ ET
BT 26.250 208.786 Td /F1 9.8 Tf  [(cardiomyopathies of gene mutations affecting ion channel function. Circulation. 2007 Nov 13;116\(20\):2325-45. Erratum in: )] TJ ET
BT 26.250 196.881 Td /F1 9.8 Tf  [(Circulation. 2008 Aug 19;118\(8\):e132. PubMed PMID: 17998470.)] TJ ET
BT 26.250 177.477 Td /F1 9.8 Tf  [(46.)] TJ ET
BT 43.553 177.477 Td /F1 9.8 Tf  [(Garratt CJ, Elliott P, Behr E, Camm AJ, Cowan C, Cruickshank S, Grace A, Griffith MJ, Jolly A, Lambiase P, McKeown P, )] TJ ET
BT 26.250 165.572 Td /F1 9.8 Tf  [(O'Callagan P, Stuart G, Watkins H; Heart Rhythm UK Familial Sudden Cardiac Death Syndromes Statement Development )] TJ ET
BT 26.250 153.667 Td /F1 9.8 Tf  [(Group. Heart Rhythm UK position statement on clinical indications for implantable cardioverter defibrillators in adult patients with )] TJ ET
BT 26.250 141.762 Td /F1 9.8 Tf  [(familial sudden cardiac death syndromes. Europace. 2010 Aug;12\(8\):1156-75. PubMed PMID: 20663787.)] TJ ET
BT 26.250 122.358 Td /F1 9.8 Tf  [(47.)] TJ ET
BT 43.553 122.358 Td /F1 9.8 Tf  [(Zipes DP, Camm AJ, Borggrefe M, Buxton AE, Chaitman B, Fromer M, Gregoratos G, Klein G, Moss AJ, Myerburg RJ, )] TJ ET
BT 26.250 110.453 Td /F1 9.8 Tf  [(Priori SG, Quinones MA, Roden DM, Silka MJ, Tracy C, Smith SC Jr, Jacobs AK, Adams CD, Antman EM, Anderson JL, Hunt )] TJ ET
BT 26.250 98.548 Td /F1 9.8 Tf  [(SA, Halperin JL, Nishimura R, Ornato JP, Page RL, Riegel B, Blanc JJ, Budaj A, Dean V, Deckers JW, Despres C, Dickstein K, )] TJ ET
BT 26.250 86.643 Td /F1 9.8 Tf  [(Lekakis J, McGregor K, Metra M, Morais J, Osterspey A, Tamargo JL, Zamorano JL; American College of Cardiology/American )] TJ ET
BT 26.250 74.739 Td /F1 9.8 Tf  [(Heart Association Task Force; European Society of Cardiology Committee for Practice Guidelines; European Heart Rhythm )] TJ ET
BT 26.250 62.834 Td /F1 9.8 Tf  [(Association; Heart Rhythm Society. ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias )] TJ ET
BT 26.250 50.929 Td /F1 9.8 Tf  [(and the Prevention of Sudden Cardiac Death: a report of the American College of Cardiology/American Heart Association Task )] TJ ET
Q
q
0.000 0.000 0.000 rg
BT 291.710 19.825 Td /F1 11.0 Tf  [(8)] TJ ET
BT 25.000 19.825 Td /F1 11.0 Tf  [(PLOS Currents Evidence on Genomic Tests)] TJ ET

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0.271 0.267 0.267 rg
q
15.000 39.263 577.500 737.737 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F1 9.8 Tf  [(Force and the European Society of Cardiology Committee for Practice Guidelines \(writing committee to develop Guidelines for )] TJ ET
BT 26.250 755.571 Td /F1 9.8 Tf  [(Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death\): developed in collaboration )] TJ ET
BT 26.250 743.667 Td /F1 9.8 Tf  [(with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation. 2006 Sep 5;114\(10\):e385-484. Epub )] TJ ET
BT 26.250 731.762 Td /F1 9.8 Tf  [(2006 Aug 25. PubMed PMID: 16935995.)] TJ ET
BT 26.250 712.357 Td /F1 9.8 Tf  [(48.)] TJ ET
BT 43.553 712.357 Td /F1 9.8 Tf  [(Priori SG, Cerrone M. Molecular genetics: is it making an impact in the management of inherited arrhythmogenic )] TJ ET
BT 26.250 700.452 Td /F1 9.8 Tf  [(syndromes? Hellenic J Cardiol. 2005 Mar-Apr;46\(2\):83-7. PubMed PMID: 15847126.)] TJ ET
BT 26.250 681.048 Td /F1 9.8 Tf  [(49.)] TJ ET
BT 43.553 681.048 Td /F1 9.8 Tf  [(John Welsh Cardiovascular Diagnostic Laboratory, Baylor College of Medicine. KCNJ2 and CAV3 mutation analysis. )] TJ ET
BT 26.250 669.143 Td /F1 9.8 Tf  [(Available at: https://www.bcm.edu/pediatrics/cardiology. Accessed 10 Mar 2011.)] TJ ET
BT 26.250 649.738 Td /F1 9.8 Tf  [(50.)] TJ ET
BT 43.553 649.738 Td /F1 9.8 Tf  [(Kapplinger JD, Tester DJ, Salisbury BA, Carr JL, Harris-Kerr C, Pollevick GD, Wilde AA, Ackerman MJ. Spectrum and )] TJ ET
BT 26.250 637.833 Td /F1 9.8 Tf  [(prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome )] TJ ET
BT 26.250 625.929 Td /F1 9.8 Tf  [(genetic test. Heart Rhythm. 2009 Sep;6\(9\):1297-303. Epub 2009 Jun 23. PubMed PMID: 19716085; PubMed Central PMCID: )] TJ ET
BT 26.250 614.024 Td /F1 9.8 Tf  [(PMC3049907.)] TJ ET
BT 26.250 594.619 Td /F1 9.8 Tf  [(51.)] TJ ET
BT 43.553 594.619 Td /F1 9.8 Tf  [(Taggart NW, Haglund CM, Tester DJ, Ackerman MJ. Diagnostic miscues in congenital long-QT syndrome. Circulation. 2007 )] TJ ET
BT 26.250 582.714 Td /F1 9.8 Tf  [(May 22;115\(20\):2613-20. Epub 2007 May 14. PubMed PMID: 17502575.)] TJ ET
BT 26.250 563.310 Td /F1 9.8 Tf  [(52.)] TJ ET
BT 43.553 563.310 Td /F1 9.8 Tf  [(Kaufman ES, Priori SG, Napolitano C, Schwartz PJ, Iyengar S, Elston RC, Schnell AH, Gorodeski EZ, Rammohan G, )] TJ ET
BT 26.250 551.405 Td /F1 9.8 Tf  [(Bahhur NO, Connuck D, Verrilli L, Rosenbaum DS, Brown AM. Electrocardiographic prediction of abnormal genotype in )] TJ ET
BT 26.250 539.500 Td /F1 9.8 Tf  [(congenital long QT syndrome: experience in 101 related family members. J Cardiovasc Electrophysiol. 2001 Apr;12\(4\):455-61. )] TJ ET
BT 26.250 527.595 Td /F1 9.8 Tf  [(PubMed PMID: 11332568.)] TJ ET
BT 26.250 508.191 Td /F1 9.8 Tf  [(53.)] TJ ET
BT 43.553 508.191 Td /F1 9.8 Tf  [(Napolitano C, Priori SG, Schwartz PJ, Bloise R, Ronchetti E, Nastoli J, Bottelli G, Cerrone M, Leonardi S. Genetic testing in )] TJ ET
BT 26.250 496.286 Td /F1 9.8 Tf  [(the long QT syndrome: development and validation of an efficient approach to genotyping in clinical practice. JAMA. 2005 Dec )] TJ ET
BT 26.250 484.381 Td /F1 9.8 Tf  [(21;294\(23\):2975-80. PubMed PMID: 16414944.)] TJ ET
BT 26.250 464.976 Td /F1 9.8 Tf  [(54.)] TJ ET
BT 43.553 464.976 Td /F1 9.8 Tf  [(Wilde AA. Long QT syndrome: a double hit hurts more. Heart Rhythm. 2010 Oct;7\(10\):1419-20. Epub 2010 Jun 22. PubMed )] TJ ET
BT 26.250 453.072 Td /F1 9.8 Tf  [(PMID: 20601150.)] TJ ET
BT 26.250 433.667 Td /F1 9.8 Tf  [(55.)] TJ ET
BT 43.553 433.667 Td /F1 9.8 Tf  [(Kapa S, Tester DJ, Salisbury BA, Harris-Kerr C, Pungliya MS, Alders M, Wilde AA, Ackerman MJ. Genetic testing for long-)] TJ ET
BT 26.250 421.762 Td /F1 9.8 Tf  [(QT syndrome: distinguishing pathogenic mutations from benign variants. Circulation. 2009 Nov 3;120\(18\):1752-60. Epub 2009 )] TJ ET
BT 26.250 409.857 Td /F1 9.8 Tf  [(Oct 19. PubMed PMID: 19841300; PubMed Central PMCID: PMC3025752.)] TJ ET
BT 26.250 390.453 Td /F1 9.8 Tf  [(56.)] TJ ET
BT 43.553 390.453 Td /F1 9.8 Tf  [(Zareba W. Genotype-specific ECG patterns in long QT syndrome. J Electrocardiol. 2006 Oct;39\(4 Suppl\):S101-6. Epub )] TJ ET
BT 26.250 378.548 Td /F1 9.8 Tf  [(2006 Sep 11. Review. PubMed PMID: 16963070.)] TJ ET
BT 26.250 359.143 Td /F1 9.8 Tf  [(57.)] TJ ET
BT 43.553 359.143 Td /F1 9.8 Tf  [(Couderc JP, McNitt S, Xia J, Zareba W, Moss AJ. Repolarization morphology in adult LQT2 carriers with borderline )] TJ ET
BT 26.250 347.238 Td /F1 9.8 Tf  [(prolonged QTc interval. Heart Rhythm. 2006 Dec;3\(12\):1460-6. Epub 2006 Aug 10. PubMed PMID: 17161789.)] TJ ET
BT 26.250 327.834 Td /F1 9.8 Tf  [(58.)] TJ ET
BT 43.553 327.834 Td /F1 9.8 Tf  [(Zhang L, Timothy KW, Vincent GM, Lehmann MH, Fox J, Giuli LC, Shen J, Splawski I, Priori SG, Compton SJ, Yanowitz F, )] TJ ET
BT 26.250 315.929 Td /F1 9.8 Tf  [(Benhorin J, Moss AJ, Schwartz PJ, Robinson JL, Wang Q, Zareba W, Keating MT, Towbin JA, Napolitano C, Medina A. )] TJ ET
BT 26.250 304.024 Td /F1 9.8 Tf  [(Spectrum of ST-T-wave patterns and repolarization parameters in congenital long-QT syndrome: ECG findings identify )] TJ ET
BT 26.250 292.119 Td /F1 9.8 Tf  [(genotypes. Circulation. 2000 Dec 5;102\(23\):2849-55. PubMed PMID: 11104743.)] TJ ET
BT 26.250 272.715 Td /F1 9.8 Tf  [(59.)] TJ ET
BT 43.553 272.715 Td /F1 9.8 Tf  [(Correlagen. Frequently asked questions about Correlagen�s CardioGeneScan \(CGS\). Available at: )] TJ ET
BT 26.250 260.810 Td /F1 9.8 Tf  [(https://www.correlagen.com/fields/cardiology/downloads/CARDIO_CRLGFAQS.pdf. Accessed 16 Mar 2011.)] TJ ET
BT 26.250 241.405 Td /F1 9.8 Tf  [(60.)] TJ ET
BT 43.553 241.405 Td /F1 9.8 Tf  [(Bai R, Napolitano C, Bloise R, Monteforte N, Priori SG. Yield of genetic screening in inherited cardiac channelopathies: how )] TJ ET
BT 26.250 229.500 Td /F1 9.8 Tf  [(to prioritize access to genetic testing. Circ Arrhythm Electrophysiol. 2009 Feb;2\(1\):6-15. Epub 2009 Feb 10. PubMed PMID: )] TJ ET
BT 26.250 217.596 Td /F1 9.8 Tf  [(19808439.)] TJ ET
BT 26.250 198.191 Td /F1 9.8 Tf  [(61.)] TJ ET
BT 43.553 198.191 Td /F1 9.8 Tf  [(Gross GJ. Management of Brugada syndrome in children. Pediatr Health 2010 Feb;4\(1\):35-43.)] TJ ET
BT 26.250 178.786 Td /F1 9.8 Tf  [(62.)] TJ ET
BT 43.553 178.786 Td /F1 9.8 Tf  [(Martini B, Cannas S, Nava A. Brugada by any other name? Eur Heart J. 2001 Oct;22\(19\):1835-6. PubMed PMID: )] TJ ET
BT 26.250 166.881 Td /F1 9.8 Tf  [(11549306.)] TJ ET
BT 26.250 147.477 Td /F1 9.8 Tf  [(63.)] TJ ET
BT 43.553 147.477 Td /F1 9.8 Tf  [(Shimizu W, Moss AJ, Wilde AA, Towbin JA, Ackerman MJ, January CT, Tester DJ, Zareba W, Robinson JL, Qi M, Vincent )] TJ ET
BT 26.250 135.572 Td /F1 9.8 Tf  [(GM, Kaufman ES, Hofman N, Noda T, Kamakura S, Miyamoto Y, Shah S, Amin V, Goldenberg I, Andrews ML, McNitt S. )] TJ ET
BT 26.250 123.667 Td /F1 9.8 Tf  [(Genotype-phenotype aspects of type 2 long QT syndrome. J Am Coll Cardiol. 2009 Nov 24;54\(22\):2052-62. PubMed PMID: )] TJ ET
BT 26.250 111.762 Td /F1 9.8 Tf  [(19926013; PubMed Central PMCID: PMC2808400.)] TJ ET
BT 26.250 92.358 Td /F1 9.8 Tf  [(64.)] TJ ET
BT 43.553 92.358 Td /F1 9.8 Tf  [(Gehi AK, Duong TD, Metz LD, Gomes JA, Mehta D. Risk stratification of individuals with the Brugada electrocardiogram: a )] TJ ET
BT 26.250 80.453 Td /F1 9.8 Tf  [(meta-analysis. J Cardiovasc Electrophysiol. 2006 Jun;17\(6\):577-83. PubMed PMID: 16836701.)] TJ ET
BT 26.250 61.048 Td /F1 9.8 Tf  [(65.)] TJ ET
BT 43.553 61.048 Td /F1 9.8 Tf  [(Nof E, Antzelevitch C. Risk stratification [corrected] of Brugada syndrome revisited. Isr Med Assoc J. 2008 Jun;10\(6\):462-4. )] TJ ET
BT 26.250 49.143 Td /F1 9.8 Tf  [(Erratum in: Isr Med Assoc J. 2008 Jul;10\(7\):549. PubMed PMID: 18669148; PubMed Central PMCID: PMC2562553.)] TJ ET
Q
q
15.000 39.263 577.500 737.737 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F1 9.8 Tf  [(Force and the European Society of Cardiology Committee for Practice Guidelines \(writing committee to develop Guidelines for )] TJ ET
BT 26.250 755.571 Td /F1 9.8 Tf  [(Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death\): developed in collaboration )] TJ ET
BT 26.250 743.667 Td /F1 9.8 Tf  [(with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation. 2006 Sep 5;114\(10\):e385-484. Epub )] TJ ET
BT 26.250 731.762 Td /F1 9.8 Tf  [(2006 Aug 25. PubMed PMID: 16935995.)] TJ ET
BT 26.250 712.357 Td /F1 9.8 Tf  [(48.)] TJ ET
BT 43.553 712.357 Td /F1 9.8 Tf  [(Priori SG, Cerrone M. Molecular genetics: is it making an impact in the management of inherited arrhythmogenic )] TJ ET
BT 26.250 700.452 Td /F1 9.8 Tf  [(syndromes? Hellenic J Cardiol. 2005 Mar-Apr;46\(2\):83-7. PubMed PMID: 15847126.)] TJ ET
BT 26.250 681.048 Td /F1 9.8 Tf  [(49.)] TJ ET
BT 43.553 681.048 Td /F1 9.8 Tf  [(John Welsh Cardiovascular Diagnostic Laboratory, Baylor College of Medicine. KCNJ2 and CAV3 mutation analysis. )] TJ ET
BT 26.250 669.143 Td /F1 9.8 Tf  [(Available at: https://www.bcm.edu/pediatrics/cardiology. Accessed 10 Mar 2011.)] TJ ET
BT 26.250 649.738 Td /F1 9.8 Tf  [(50.)] TJ ET
BT 43.553 649.738 Td /F1 9.8 Tf  [(Kapplinger JD, Tester DJ, Salisbury BA, Carr JL, Harris-Kerr C, Pollevick GD, Wilde AA, Ackerman MJ. Spectrum and )] TJ ET
BT 26.250 637.833 Td /F1 9.8 Tf  [(prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome )] TJ ET
BT 26.250 625.929 Td /F1 9.8 Tf  [(genetic test. Heart Rhythm. 2009 Sep;6\(9\):1297-303. Epub 2009 Jun 23. PubMed PMID: 19716085; PubMed Central PMCID: )] TJ ET
BT 26.250 614.024 Td /F1 9.8 Tf  [(PMC3049907.)] TJ ET
BT 26.250 594.619 Td /F1 9.8 Tf  [(51.)] TJ ET
BT 43.553 594.619 Td /F1 9.8 Tf  [(Taggart NW, Haglund CM, Tester DJ, Ackerman MJ. Diagnostic miscues in congenital long-QT syndrome. Circulation. 2007 )] TJ ET
BT 26.250 582.714 Td /F1 9.8 Tf  [(May 22;115\(20\):2613-20. Epub 2007 May 14. PubMed PMID: 17502575.)] TJ ET
BT 26.250 563.310 Td /F1 9.8 Tf  [(52.)] TJ ET
BT 43.553 563.310 Td /F1 9.8 Tf  [(Kaufman ES, Priori SG, Napolitano C, Schwartz PJ, Iyengar S, Elston RC, Schnell AH, Gorodeski EZ, Rammohan G, )] TJ ET
BT 26.250 551.405 Td /F1 9.8 Tf  [(Bahhur NO, Connuck D, Verrilli L, Rosenbaum DS, Brown AM. Electrocardiographic prediction of abnormal genotype in )] TJ ET
BT 26.250 539.500 Td /F1 9.8 Tf  [(congenital long QT syndrome: experience in 101 related family members. J Cardiovasc Electrophysiol. 2001 Apr;12\(4\):455-61. )] TJ ET
BT 26.250 527.595 Td /F1 9.8 Tf  [(PubMed PMID: 11332568.)] TJ ET
BT 26.250 508.191 Td /F1 9.8 Tf  [(53.)] TJ ET
BT 43.553 508.191 Td /F1 9.8 Tf  [(Napolitano C, Priori SG, Schwartz PJ, Bloise R, Ronchetti E, Nastoli J, Bottelli G, Cerrone M, Leonardi S. Genetic testing in )] TJ ET
BT 26.250 496.286 Td /F1 9.8 Tf  [(the long QT syndrome: development and validation of an efficient approach to genotyping in clinical practice. JAMA. 2005 Dec )] TJ ET
BT 26.250 484.381 Td /F1 9.8 Tf  [(21;294\(23\):2975-80. PubMed PMID: 16414944.)] TJ ET
BT 26.250 464.976 Td /F1 9.8 Tf  [(54.)] TJ ET
BT 43.553 464.976 Td /F1 9.8 Tf  [(Wilde AA. Long QT syndrome: a double hit hurts more. Heart Rhythm. 2010 Oct;7\(10\):1419-20. Epub 2010 Jun 22. PubMed )] TJ ET
BT 26.250 453.072 Td /F1 9.8 Tf  [(PMID: 20601150.)] TJ ET
BT 26.250 433.667 Td /F1 9.8 Tf  [(55.)] TJ ET
BT 43.553 433.667 Td /F1 9.8 Tf  [(Kapa S, Tester DJ, Salisbury BA, Harris-Kerr C, Pungliya MS, Alders M, Wilde AA, Ackerman MJ. Genetic testing for long-)] TJ ET
BT 26.250 421.762 Td /F1 9.8 Tf  [(QT syndrome: distinguishing pathogenic mutations from benign variants. Circulation. 2009 Nov 3;120\(18\):1752-60. Epub 2009 )] TJ ET
BT 26.250 409.857 Td /F1 9.8 Tf  [(Oct 19. PubMed PMID: 19841300; PubMed Central PMCID: PMC3025752.)] TJ ET
BT 26.250 390.453 Td /F1 9.8 Tf  [(56.)] TJ ET
BT 43.553 390.453 Td /F1 9.8 Tf  [(Zareba W. Genotype-specific ECG patterns in long QT syndrome. J Electrocardiol. 2006 Oct;39\(4 Suppl\):S101-6. Epub )] TJ ET
BT 26.250 378.548 Td /F1 9.8 Tf  [(2006 Sep 11. Review. PubMed PMID: 16963070.)] TJ ET
BT 26.250 359.143 Td /F1 9.8 Tf  [(57.)] TJ ET
BT 43.553 359.143 Td /F1 9.8 Tf  [(Couderc JP, McNitt S, Xia J, Zareba W, Moss AJ. Repolarization morphology in adult LQT2 carriers with borderline )] TJ ET
BT 26.250 347.238 Td /F1 9.8 Tf  [(prolonged QTc interval. Heart Rhythm. 2006 Dec;3\(12\):1460-6. Epub 2006 Aug 10. PubMed PMID: 17161789.)] TJ ET
BT 26.250 327.834 Td /F1 9.8 Tf  [(58.)] TJ ET
BT 43.553 327.834 Td /F1 9.8 Tf  [(Zhang L, Timothy KW, Vincent GM, Lehmann MH, Fox J, Giuli LC, Shen J, Splawski I, Priori SG, Compton SJ, Yanowitz F, )] TJ ET
BT 26.250 315.929 Td /F1 9.8 Tf  [(Benhorin J, Moss AJ, Schwartz PJ, Robinson JL, Wang Q, Zareba W, Keating MT, Towbin JA, Napolitano C, Medina A. )] TJ ET
BT 26.250 304.024 Td /F1 9.8 Tf  [(Spectrum of ST-T-wave patterns and repolarization parameters in congenital long-QT syndrome: ECG findings identify )] TJ ET
BT 26.250 292.119 Td /F1 9.8 Tf  [(genotypes. Circulation. 2000 Dec 5;102\(23\):2849-55. PubMed PMID: 11104743.)] TJ ET
BT 26.250 272.715 Td /F1 9.8 Tf  [(59.)] TJ ET
BT 43.553 272.715 Td /F1 9.8 Tf  [(Correlagen. Frequently asked questions about Correlagen�s CardioGeneScan \(CGS\). Available at: )] TJ ET
BT 26.250 260.810 Td /F1 9.8 Tf  [(https://www.correlagen.com/fields/cardiology/downloads/CARDIO_CRLGFAQS.pdf. Accessed 16 Mar 2011.)] TJ ET
BT 26.250 241.405 Td /F1 9.8 Tf  [(60.)] TJ ET
BT 43.553 241.405 Td /F1 9.8 Tf  [(Bai R, Napolitano C, Bloise R, Monteforte N, Priori SG. Yield of genetic screening in inherited cardiac channelopathies: how )] TJ ET
BT 26.250 229.500 Td /F1 9.8 Tf  [(to prioritize access to genetic testing. Circ Arrhythm Electrophysiol. 2009 Feb;2\(1\):6-15. Epub 2009 Feb 10. PubMed PMID: )] TJ ET
BT 26.250 217.596 Td /F1 9.8 Tf  [(19808439.)] TJ ET
BT 26.250 198.191 Td /F1 9.8 Tf  [(61.)] TJ ET
BT 43.553 198.191 Td /F1 9.8 Tf  [(Gross GJ. Management of Brugada syndrome in children. Pediatr Health 2010 Feb;4\(1\):35-43.)] TJ ET
BT 26.250 178.786 Td /F1 9.8 Tf  [(62.)] TJ ET
BT 43.553 178.786 Td /F1 9.8 Tf  [(Martini B, Cannas S, Nava A. Brugada by any other name? Eur Heart J. 2001 Oct;22\(19\):1835-6. PubMed PMID: )] TJ ET
BT 26.250 166.881 Td /F1 9.8 Tf  [(11549306.)] TJ ET
BT 26.250 147.477 Td /F1 9.8 Tf  [(63.)] TJ ET
BT 43.553 147.477 Td /F1 9.8 Tf  [(Shimizu W, Moss AJ, Wilde AA, Towbin JA, Ackerman MJ, January CT, Tester DJ, Zareba W, Robinson JL, Qi M, Vincent )] TJ ET
BT 26.250 135.572 Td /F1 9.8 Tf  [(GM, Kaufman ES, Hofman N, Noda T, Kamakura S, Miyamoto Y, Shah S, Amin V, Goldenberg I, Andrews ML, McNitt S. )] TJ ET
BT 26.250 123.667 Td /F1 9.8 Tf  [(Genotype-phenotype aspects of type 2 long QT syndrome. J Am Coll Cardiol. 2009 Nov 24;54\(22\):2052-62. PubMed PMID: )] TJ ET
BT 26.250 111.762 Td /F1 9.8 Tf  [(19926013; PubMed Central PMCID: PMC2808400.)] TJ ET
BT 26.250 92.358 Td /F1 9.8 Tf  [(64.)] TJ ET
BT 43.553 92.358 Td /F1 9.8 Tf  [(Gehi AK, Duong TD, Metz LD, Gomes JA, Mehta D. Risk stratification of individuals with the Brugada electrocardiogram: a )] TJ ET
BT 26.250 80.453 Td /F1 9.8 Tf  [(meta-analysis. J Cardiovasc Electrophysiol. 2006 Jun;17\(6\):577-83. PubMed PMID: 16836701.)] TJ ET
BT 26.250 61.048 Td /F1 9.8 Tf  [(65.)] TJ ET
BT 43.553 61.048 Td /F1 9.8 Tf  [(Nof E, Antzelevitch C. Risk stratification [corrected] of Brugada syndrome revisited. Isr Med Assoc J. 2008 Jun;10\(6\):462-4. )] TJ ET
BT 26.250 49.143 Td /F1 9.8 Tf  [(Erratum in: Isr Med Assoc J. 2008 Jul;10\(7\):549. PubMed PMID: 18669148; PubMed Central PMCID: PMC2562553.)] TJ ET
Q
q
15.000 39.263 577.500 737.737 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F1 9.8 Tf  [(Force and the European Society of Cardiology Committee for Practice Guidelines \(writing committee to develop Guidelines for )] TJ ET
BT 26.250 755.571 Td /F1 9.8 Tf  [(Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death\): developed in collaboration )] TJ ET
BT 26.250 743.667 Td /F1 9.8 Tf  [(with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation. 2006 Sep 5;114\(10\):e385-484. Epub )] TJ ET
BT 26.250 731.762 Td /F1 9.8 Tf  [(2006 Aug 25. PubMed PMID: 16935995.)] TJ ET
BT 26.250 712.357 Td /F1 9.8 Tf  [(48.)] TJ ET
BT 43.553 712.357 Td /F1 9.8 Tf  [(Priori SG, Cerrone M. Molecular genetics: is it making an impact in the management of inherited arrhythmogenic )] TJ ET
BT 26.250 700.452 Td /F1 9.8 Tf  [(syndromes? Hellenic J Cardiol. 2005 Mar-Apr;46\(2\):83-7. PubMed PMID: 15847126.)] TJ ET
BT 26.250 681.048 Td /F1 9.8 Tf  [(49.)] TJ ET
BT 43.553 681.048 Td /F1 9.8 Tf  [(John Welsh Cardiovascular Diagnostic Laboratory, Baylor College of Medicine. KCNJ2 and CAV3 mutation analysis. )] TJ ET
BT 26.250 669.143 Td /F1 9.8 Tf  [(Available at: https://www.bcm.edu/pediatrics/cardiology. Accessed 10 Mar 2011.)] TJ ET
BT 26.250 649.738 Td /F1 9.8 Tf  [(50.)] TJ ET
BT 43.553 649.738 Td /F1 9.8 Tf  [(Kapplinger JD, Tester DJ, Salisbury BA, Carr JL, Harris-Kerr C, Pollevick GD, Wilde AA, Ackerman MJ. Spectrum and )] TJ ET
BT 26.250 637.833 Td /F1 9.8 Tf  [(prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome )] TJ ET
BT 26.250 625.929 Td /F1 9.8 Tf  [(genetic test. Heart Rhythm. 2009 Sep;6\(9\):1297-303. Epub 2009 Jun 23. PubMed PMID: 19716085; PubMed Central PMCID: )] TJ ET
BT 26.250 614.024 Td /F1 9.8 Tf  [(PMC3049907.)] TJ ET
BT 26.250 594.619 Td /F1 9.8 Tf  [(51.)] TJ ET
BT 43.553 594.619 Td /F1 9.8 Tf  [(Taggart NW, Haglund CM, Tester DJ, Ackerman MJ. Diagnostic miscues in congenital long-QT syndrome. Circulation. 2007 )] TJ ET
BT 26.250 582.714 Td /F1 9.8 Tf  [(May 22;115\(20\):2613-20. Epub 2007 May 14. PubMed PMID: 17502575.)] TJ ET
BT 26.250 563.310 Td /F1 9.8 Tf  [(52.)] TJ ET
BT 43.553 563.310 Td /F1 9.8 Tf  [(Kaufman ES, Priori SG, Napolitano C, Schwartz PJ, Iyengar S, Elston RC, Schnell AH, Gorodeski EZ, Rammohan G, )] TJ ET
BT 26.250 551.405 Td /F1 9.8 Tf  [(Bahhur NO, Connuck D, Verrilli L, Rosenbaum DS, Brown AM. Electrocardiographic prediction of abnormal genotype in )] TJ ET
BT 26.250 539.500 Td /F1 9.8 Tf  [(congenital long QT syndrome: experience in 101 related family members. J Cardiovasc Electrophysiol. 2001 Apr;12\(4\):455-61. )] TJ ET
BT 26.250 527.595 Td /F1 9.8 Tf  [(PubMed PMID: 11332568.)] TJ ET
BT 26.250 508.191 Td /F1 9.8 Tf  [(53.)] TJ ET
BT 43.553 508.191 Td /F1 9.8 Tf  [(Napolitano C, Priori SG, Schwartz PJ, Bloise R, Ronchetti E, Nastoli J, Bottelli G, Cerrone M, Leonardi S. Genetic testing in )] TJ ET
BT 26.250 496.286 Td /F1 9.8 Tf  [(the long QT syndrome: development and validation of an efficient approach to genotyping in clinical practice. JAMA. 2005 Dec )] TJ ET
BT 26.250 484.381 Td /F1 9.8 Tf  [(21;294\(23\):2975-80. PubMed PMID: 16414944.)] TJ ET
BT 26.250 464.976 Td /F1 9.8 Tf  [(54.)] TJ ET
BT 43.553 464.976 Td /F1 9.8 Tf  [(Wilde AA. Long QT syndrome: a double hit hurts more. Heart Rhythm. 2010 Oct;7\(10\):1419-20. Epub 2010 Jun 22. PubMed )] TJ ET
BT 26.250 453.072 Td /F1 9.8 Tf  [(PMID: 20601150.)] TJ ET
BT 26.250 433.667 Td /F1 9.8 Tf  [(55.)] TJ ET
BT 43.553 433.667 Td /F1 9.8 Tf  [(Kapa S, Tester DJ, Salisbury BA, Harris-Kerr C, Pungliya MS, Alders M, Wilde AA, Ackerman MJ. Genetic testing for long-)] TJ ET
BT 26.250 421.762 Td /F1 9.8 Tf  [(QT syndrome: distinguishing pathogenic mutations from benign variants. Circulation. 2009 Nov 3;120\(18\):1752-60. Epub 2009 )] TJ ET
BT 26.250 409.857 Td /F1 9.8 Tf  [(Oct 19. PubMed PMID: 19841300; PubMed Central PMCID: PMC3025752.)] TJ ET
BT 26.250 390.453 Td /F1 9.8 Tf  [(56.)] TJ ET
BT 43.553 390.453 Td /F1 9.8 Tf  [(Zareba W. Genotype-specific ECG patterns in long QT syndrome. J Electrocardiol. 2006 Oct;39\(4 Suppl\):S101-6. Epub )] TJ ET
BT 26.250 378.548 Td /F1 9.8 Tf  [(2006 Sep 11. Review. PubMed PMID: 16963070.)] TJ ET
BT 26.250 359.143 Td /F1 9.8 Tf  [(57.)] TJ ET
BT 43.553 359.143 Td /F1 9.8 Tf  [(Couderc JP, McNitt S, Xia J, Zareba W, Moss AJ. Repolarization morphology in adult LQT2 carriers with borderline )] TJ ET
BT 26.250 347.238 Td /F1 9.8 Tf  [(prolonged QTc interval. Heart Rhythm. 2006 Dec;3\(12\):1460-6. Epub 2006 Aug 10. PubMed PMID: 17161789.)] TJ ET
BT 26.250 327.834 Td /F1 9.8 Tf  [(58.)] TJ ET
BT 43.553 327.834 Td /F1 9.8 Tf  [(Zhang L, Timothy KW, Vincent GM, Lehmann MH, Fox J, Giuli LC, Shen J, Splawski I, Priori SG, Compton SJ, Yanowitz F, )] TJ ET
BT 26.250 315.929 Td /F1 9.8 Tf  [(Benhorin J, Moss AJ, Schwartz PJ, Robinson JL, Wang Q, Zareba W, Keating MT, Towbin JA, Napolitano C, Medina A. )] TJ ET
BT 26.250 304.024 Td /F1 9.8 Tf  [(Spectrum of ST-T-wave patterns and repolarization parameters in congenital long-QT syndrome: ECG findings identify )] TJ ET
BT 26.250 292.119 Td /F1 9.8 Tf  [(genotypes. Circulation. 2000 Dec 5;102\(23\):2849-55. PubMed PMID: 11104743.)] TJ ET
BT 26.250 272.715 Td /F1 9.8 Tf  [(59.)] TJ ET
BT 43.553 272.715 Td /F1 9.8 Tf  [(Correlagen. Frequently asked questions about Correlagen�s CardioGeneScan \(CGS\). Available at: )] TJ ET
BT 26.250 260.810 Td /F1 9.8 Tf  [(https://www.correlagen.com/fields/cardiology/downloads/CARDIO_CRLGFAQS.pdf. Accessed 16 Mar 2011.)] TJ ET
BT 26.250 241.405 Td /F1 9.8 Tf  [(60.)] TJ ET
BT 43.553 241.405 Td /F1 9.8 Tf  [(Bai R, Napolitano C, Bloise R, Monteforte N, Priori SG. Yield of genetic screening in inherited cardiac channelopathies: how )] TJ ET
BT 26.250 229.500 Td /F1 9.8 Tf  [(to prioritize access to genetic testing. Circ Arrhythm Electrophysiol. 2009 Feb;2\(1\):6-15. Epub 2009 Feb 10. PubMed PMID: )] TJ ET
BT 26.250 217.596 Td /F1 9.8 Tf  [(19808439.)] TJ ET
BT 26.250 198.191 Td /F1 9.8 Tf  [(61.)] TJ ET
BT 43.553 198.191 Td /F1 9.8 Tf  [(Gross GJ. Management of Brugada syndrome in children. Pediatr Health 2010 Feb;4\(1\):35-43.)] TJ ET
BT 26.250 178.786 Td /F1 9.8 Tf  [(62.)] TJ ET
BT 43.553 178.786 Td /F1 9.8 Tf  [(Martini B, Cannas S, Nava A. Brugada by any other name? Eur Heart J. 2001 Oct;22\(19\):1835-6. PubMed PMID: )] TJ ET
BT 26.250 166.881 Td /F1 9.8 Tf  [(11549306.)] TJ ET
BT 26.250 147.477 Td /F1 9.8 Tf  [(63.)] TJ ET
BT 43.553 147.477 Td /F1 9.8 Tf  [(Shimizu W, Moss AJ, Wilde AA, Towbin JA, Ackerman MJ, January CT, Tester DJ, Zareba W, Robinson JL, Qi M, Vincent )] TJ ET
BT 26.250 135.572 Td /F1 9.8 Tf  [(GM, Kaufman ES, Hofman N, Noda T, Kamakura S, Miyamoto Y, Shah S, Amin V, Goldenberg I, Andrews ML, McNitt S. )] TJ ET
BT 26.250 123.667 Td /F1 9.8 Tf  [(Genotype-phenotype aspects of type 2 long QT syndrome. J Am Coll Cardiol. 2009 Nov 24;54\(22\):2052-62. PubMed PMID: )] TJ ET
BT 26.250 111.762 Td /F1 9.8 Tf  [(19926013; PubMed Central PMCID: PMC2808400.)] TJ ET
BT 26.250 92.358 Td /F1 9.8 Tf  [(64.)] TJ ET
BT 43.553 92.358 Td /F1 9.8 Tf  [(Gehi AK, Duong TD, Metz LD, Gomes JA, Mehta D. Risk stratification of individuals with the Brugada electrocardiogram: a )] TJ ET
BT 26.250 80.453 Td /F1 9.8 Tf  [(meta-analysis. J Cardiovasc Electrophysiol. 2006 Jun;17\(6\):577-83. PubMed PMID: 16836701.)] TJ ET
BT 26.250 61.048 Td /F1 9.8 Tf  [(65.)] TJ ET
BT 43.553 61.048 Td /F1 9.8 Tf  [(Nof E, Antzelevitch C. Risk stratification [corrected] of Brugada syndrome revisited. Isr Med Assoc J. 2008 Jun;10\(6\):462-4. )] TJ ET
BT 26.250 49.143 Td /F1 9.8 Tf  [(Erratum in: Isr Med Assoc J. 2008 Jul;10\(7\):549. PubMed PMID: 18669148; PubMed Central PMCID: PMC2562553.)] TJ ET
Q
q
0.000 0.000 0.000 rg
BT 291.710 19.825 Td /F1 11.0 Tf  [(9)] TJ ET
BT 25.000 19.825 Td /F1 11.0 Tf  [(PLOS Currents Evidence on Genomic Tests)] TJ ET

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0.271 0.267 0.267 rg
q
15.000 197.120 577.500 579.880 re W n
0.271 0.267 0.267 rg
BT 26.250 759.976 Td /F1 9.8 Tf  [(66.)] TJ ET
BT 43.553 759.976 Td /F1 9.8 Tf  [(Vincent GM. Genotyping has a minor role in selecting therapy for congenital long-QT syndromes at present. Circ Arrhythm )] TJ ET
BT 26.250 748.071 Td /F1 9.8 Tf  [(Electrophysiol. 2008 Aug;1\(3\):227-33; discussion 233. Review. PubMed PMID: 19808413.)] TJ ET
BT 26.250 728.667 Td /F1 9.8 Tf  [(67.)] TJ ET
BT 43.553 728.667 Td /F1 9.8 Tf  [(Moss AJ, Windle JR, Hall WJ, Zareba W, Robinson JL, McNitt S, Severski P, Rosero S, Daubert JP, Qi M, Cieciorka M, )] TJ ET
BT 26.250 716.762 Td /F1 9.8 Tf  [(Manalan AS. Safety and efficacy of flecainide in subjects with Long QT-3 syndrome \(DeltaKPQ mutation\): a randomized, double-)] TJ ET
BT 26.250 704.857 Td /F1 9.8 Tf  [(blind, placebo-controlled clinical trial. Ann Noninvasive Electrocardiol. 2005 Oct;10\(4 Suppl\):59-66. PubMed PMID: 16274417.)] TJ ET
BT 26.250 685.452 Td /F1 9.8 Tf  [(68.)] TJ ET
BT 43.553 685.452 Td /F1 9.8 Tf  [(Ruan Y, Liu N, Bloise R, Napolitano C, Priori SG. Gating properties of SCN5A mutations and the response to mexiletine in )] TJ ET
BT 26.250 673.548 Td /F1 9.8 Tf  [(long-QT syndrome type 3 patients. Circulation. 2007 Sep 4;116\(10\):1137-44. Epub 2007 Aug 13. PubMed PMID: 17698727.)] TJ ET
BT 26.250 654.143 Td /F1 9.8 Tf  [(69.)] TJ ET
BT 43.553 654.143 Td /F1 9.8 Tf  [(Etheridge SP, Sanatani S, Cohen MI, Albaro CA, Saarel EV, Bradley DJ. Long QT syndrome in children in the era of )] TJ ET
BT 26.250 642.238 Td /F1 9.8 Tf  [(implantable defibrillators. J Am Coll Cardiol. 2007 Oct 2;50\(14\):1335-40. Epub 2007 Sep 17. PubMed PMID: 17903632.)] TJ ET
BT 26.250 622.833 Td /F1 9.8 Tf  [(70.)] TJ ET
BT 43.553 622.833 Td /F1 9.8 Tf  [(Pott C, Dechering DG, Reinke F, Muszynski A, Zellerhoff S, Bittner A, K�be J, Wasmer K, Schulze-Bahr E, M�nnig G, )] TJ ET
BT 26.250 610.929 Td /F1 9.8 Tf  [(Kotthoff S, Eckardt L. Successful treatment of catecholaminergic polymorphic ventricular tachycardia with flecainide: a case )] TJ ET
BT 26.250 599.024 Td /F1 9.8 Tf  [(report and review of the current literature. Europace. 2011 Jun;13\(6\):897-901. Epub 2011 Feb 2. Review. PubMed PMID: )] TJ ET
BT 26.250 587.119 Td /F1 9.8 Tf  [(21292648.)] TJ ET
BT 26.250 567.714 Td /F1 9.8 Tf  [(71.)] TJ ET
BT 43.553 567.714 Td /F1 9.8 Tf  [(Wilde AA, Pinto YM. Cost-effectiveness of genotyping in inherited arrhythmia syndromes: are we getting value for the )] TJ ET
BT 26.250 555.810 Td /F1 9.8 Tf  [(money? Circ Arrhythm Electrophysiol. 2009 Feb;2\(1\):1-3. PubMed PMID: 19808437.)] TJ ET
BT 26.250 536.405 Td /F1 9.8 Tf  [(72.)] TJ ET
BT 43.553 536.405 Td /F1 9.8 Tf  [(Van Langen IM, Birnie E, Alders M, Jongbloed RJ, Le Marec H, Wilde AA. The use of genotype-phenotype correlations in )] TJ ET
BT 26.250 524.500 Td /F1 9.8 Tf  [(mutation analysis for the long QT syndrome. J Med Genet. 2003 Feb;40\(2\):141-5. PubMed PMID: 12566525; PubMed Central )] TJ ET
BT 26.250 512.595 Td /F1 9.8 Tf  [(PMCID: PMC1735373.)] TJ ET
BT 26.250 493.191 Td /F1 9.8 Tf  [(73.)] TJ ET
BT 43.553 493.191 Td /F1 9.8 Tf  [(Phillips KA, Ackerman MJ, Sakowski J, Berul CI. Cost-effectiveness analysis of genetic testing for familial long QT )] TJ ET
BT 26.250 481.286 Td /F1 9.8 Tf  [(syndrome in symptomatic index cases. Heart Rhythm. 2005 Dec;2\(12\):1294-300. PubMed PMID: 16360080.)] TJ ET
BT 26.250 461.881 Td /F1 9.8 Tf  [(74.)] TJ ET
BT 43.553 461.881 Td /F1 9.8 Tf  [(Kaufman ES. Efficient genotyping for congenital long QT syndrome. JAMA. 2005 Dec 21;294\(23\):3027-8. PubMed PMID: )] TJ ET
BT 26.250 449.976 Td /F1 9.8 Tf  [(16414952.)] TJ ET
BT 26.250 430.572 Td /F1 9.8 Tf  [(75.)] TJ ET
BT 43.553 430.572 Td /F1 9.8 Tf  [(Perez MV, Kumarasamy NA, Owens DK, Wang PJ, Hlatky MA. Cost-effectiveness of genetic testing in family members of )] TJ ET
BT 26.250 418.667 Td /F1 9.8 Tf  [(patients with long-QT syndrome. Circ Cardiovasc Qual Outcomes. 2011 Jan 1;4\(1\):76-84. Epub 2010 Dec 7. PubMed PMID: )] TJ ET
BT 26.250 406.762 Td /F1 9.8 Tf  [(21139095.)] TJ ET
BT 26.250 387.357 Td /F1 9.8 Tf  [(76.)] TJ ET
BT 43.553 387.357 Td /F1 9.8 Tf  [(Medica. Genetic testing for cardiac channelopathies: utilization management policy \(number III-DIA.05\). Available at: )] TJ ET
BT 26.250 375.453 Td /F1 9.8 Tf  [(https://provider.medica.com/C10/PolicyUtilization/Document%20Library/IIIDIA05.pdf. Accessed 20 Feb 2012.)] TJ ET
BT 26.250 356.048 Td /F1 9.8 Tf  [(77.)] TJ ET
BT 43.553 356.048 Td /F1 9.8 Tf  [(Hall AE, Burton H. Legal and ethical implications of inherited cardiac disease in clinical practice within the UK. J Med Ethics. )] TJ ET
BT 26.250 344.143 Td /F1 9.8 Tf  [(2010 Dec;36\(12\):762-6. PubMed PMID: 21112937.)] TJ ET
BT 26.250 324.738 Td /F1 9.8 Tf  [(78.)] TJ ET
BT 43.553 324.738 Td /F1 9.8 Tf  [(Liebman J. Some legal, social, and ethical issues related to the genetic testing revolution, as exemplified in the long QT )] TJ ET
BT 26.250 312.834 Td /F1 9.8 Tf  [(syndrome. J Electrocardiol. 2001;34 Suppl:183-8. PubMed PMID: 11781954.)] TJ ET
BT 26.250 293.429 Td /F1 9.8 Tf  [(79.)] TJ ET
BT 43.553 293.429 Td /F1 9.8 Tf  [(Wren C. Screening children with a family history of sudden cardiac death. Heart. 2006 Jul;92\(7\):1001-6. Review. PubMed )] TJ ET
BT 26.250 281.524 Td /F1 9.8 Tf  [(PMID: 16775115; PubMed Central PMCID: PMC1860723.)] TJ ET
BT 26.250 262.119 Td /F1 9.8 Tf  [(80.)] TJ ET
BT 43.553 262.119 Td /F1 9.8 Tf  [(Schwartz PJ, Spazzolini C, Priori SG, Crotti L, Vicentini A, Landolina M, Gasparini M, Wilde AA, Knops RE, Denjoy I, )] TJ ET
BT 26.250 250.215 Td /F1 9.8 Tf  [(Toivonen L, M�nnig G, Al-Fayyadh M, Jordaens L, Borggrefe M, Holmgren C, Brugada P, De Roy L, Hohnloser SH, Brink PA. )] TJ ET
BT 26.250 238.310 Td /F1 9.8 Tf  [(Who are the long-QT syndrome patients who receive an implantable cardioverter-defibrillator and what happens to them?: data )] TJ ET
BT 26.250 226.405 Td /F1 9.8 Tf  [(from the European Long-QT Syndrome Implantable Cardioverter-Defibrillator \(LQTS ICD\) Registry. Circulation. 2010 Sep )] TJ ET
BT 26.250 214.500 Td /F1 9.8 Tf  [(28;122\(13\):1272-82. Epub 2010 Sep 13. PubMed PMID: 20837891.)] TJ ET
Q
q
15.000 197.120 577.500 579.880 re W n
0.271 0.267 0.267 rg
BT 26.250 759.976 Td /F1 9.8 Tf  [(66.)] TJ ET
BT 43.553 759.976 Td /F1 9.8 Tf  [(Vincent GM. Genotyping has a minor role in selecting therapy for congenital long-QT syndromes at present. Circ Arrhythm )] TJ ET
BT 26.250 748.071 Td /F1 9.8 Tf  [(Electrophysiol. 2008 Aug;1\(3\):227-33; discussion 233. Review. PubMed PMID: 19808413.)] TJ ET
BT 26.250 728.667 Td /F1 9.8 Tf  [(67.)] TJ ET
BT 43.553 728.667 Td /F1 9.8 Tf  [(Moss AJ, Windle JR, Hall WJ, Zareba W, Robinson JL, McNitt S, Severski P, Rosero S, Daubert JP, Qi M, Cieciorka M, )] TJ ET
BT 26.250 716.762 Td /F1 9.8 Tf  [(Manalan AS. Safety and efficacy of flecainide in subjects with Long QT-3 syndrome \(DeltaKPQ mutation\): a randomized, double-)] TJ ET
BT 26.250 704.857 Td /F1 9.8 Tf  [(blind, placebo-controlled clinical trial. Ann Noninvasive Electrocardiol. 2005 Oct;10\(4 Suppl\):59-66. PubMed PMID: 16274417.)] TJ ET
BT 26.250 685.452 Td /F1 9.8 Tf  [(68.)] TJ ET
BT 43.553 685.452 Td /F1 9.8 Tf  [(Ruan Y, Liu N, Bloise R, Napolitano C, Priori SG. Gating properties of SCN5A mutations and the response to mexiletine in )] TJ ET
BT 26.250 673.548 Td /F1 9.8 Tf  [(long-QT syndrome type 3 patients. Circulation. 2007 Sep 4;116\(10\):1137-44. Epub 2007 Aug 13. PubMed PMID: 17698727.)] TJ ET
BT 26.250 654.143 Td /F1 9.8 Tf  [(69.)] TJ ET
BT 43.553 654.143 Td /F1 9.8 Tf  [(Etheridge SP, Sanatani S, Cohen MI, Albaro CA, Saarel EV, Bradley DJ. Long QT syndrome in children in the era of )] TJ ET
BT 26.250 642.238 Td /F1 9.8 Tf  [(implantable defibrillators. J Am Coll Cardiol. 2007 Oct 2;50\(14\):1335-40. Epub 2007 Sep 17. PubMed PMID: 17903632.)] TJ ET
BT 26.250 622.833 Td /F1 9.8 Tf  [(70.)] TJ ET
BT 43.553 622.833 Td /F1 9.8 Tf  [(Pott C, Dechering DG, Reinke F, Muszynski A, Zellerhoff S, Bittner A, K�be J, Wasmer K, Schulze-Bahr E, M�nnig G, )] TJ ET
BT 26.250 610.929 Td /F1 9.8 Tf  [(Kotthoff S, Eckardt L. Successful treatment of catecholaminergic polymorphic ventricular tachycardia with flecainide: a case )] TJ ET
BT 26.250 599.024 Td /F1 9.8 Tf  [(report and review of the current literature. Europace. 2011 Jun;13\(6\):897-901. Epub 2011 Feb 2. Review. PubMed PMID: )] TJ ET
BT 26.250 587.119 Td /F1 9.8 Tf  [(21292648.)] TJ ET
BT 26.250 567.714 Td /F1 9.8 Tf  [(71.)] TJ ET
BT 43.553 567.714 Td /F1 9.8 Tf  [(Wilde AA, Pinto YM. Cost-effectiveness of genotyping in inherited arrhythmia syndromes: are we getting value for the )] TJ ET
BT 26.250 555.810 Td /F1 9.8 Tf  [(money? Circ Arrhythm Electrophysiol. 2009 Feb;2\(1\):1-3. PubMed PMID: 19808437.)] TJ ET
BT 26.250 536.405 Td /F1 9.8 Tf  [(72.)] TJ ET
BT 43.553 536.405 Td /F1 9.8 Tf  [(Van Langen IM, Birnie E, Alders M, Jongbloed RJ, Le Marec H, Wilde AA. The use of genotype-phenotype correlations in )] TJ ET
BT 26.250 524.500 Td /F1 9.8 Tf  [(mutation analysis for the long QT syndrome. J Med Genet. 2003 Feb;40\(2\):141-5. PubMed PMID: 12566525; PubMed Central )] TJ ET
BT 26.250 512.595 Td /F1 9.8 Tf  [(PMCID: PMC1735373.)] TJ ET
BT 26.250 493.191 Td /F1 9.8 Tf  [(73.)] TJ ET
BT 43.553 493.191 Td /F1 9.8 Tf  [(Phillips KA, Ackerman MJ, Sakowski J, Berul CI. Cost-effectiveness analysis of genetic testing for familial long QT )] TJ ET
BT 26.250 481.286 Td /F1 9.8 Tf  [(syndrome in symptomatic index cases. Heart Rhythm. 2005 Dec;2\(12\):1294-300. PubMed PMID: 16360080.)] TJ ET
BT 26.250 461.881 Td /F1 9.8 Tf  [(74.)] TJ ET
BT 43.553 461.881 Td /F1 9.8 Tf  [(Kaufman ES. Efficient genotyping for congenital long QT syndrome. JAMA. 2005 Dec 21;294\(23\):3027-8. PubMed PMID: )] TJ ET
BT 26.250 449.976 Td /F1 9.8 Tf  [(16414952.)] TJ ET
BT 26.250 430.572 Td /F1 9.8 Tf  [(75.)] TJ ET
BT 43.553 430.572 Td /F1 9.8 Tf  [(Perez MV, Kumarasamy NA, Owens DK, Wang PJ, Hlatky MA. Cost-effectiveness of genetic testing in family members of )] TJ ET
BT 26.250 418.667 Td /F1 9.8 Tf  [(patients with long-QT syndrome. Circ Cardiovasc Qual Outcomes. 2011 Jan 1;4\(1\):76-84. Epub 2010 Dec 7. PubMed PMID: )] TJ ET
BT 26.250 406.762 Td /F1 9.8 Tf  [(21139095.)] TJ ET
BT 26.250 387.357 Td /F1 9.8 Tf  [(76.)] TJ ET
BT 43.553 387.357 Td /F1 9.8 Tf  [(Medica. Genetic testing for cardiac channelopathies: utilization management policy \(number III-DIA.05\). Available at: )] TJ ET
BT 26.250 375.453 Td /F1 9.8 Tf  [(https://provider.medica.com/C10/PolicyUtilization/Document%20Library/IIIDIA05.pdf. Accessed 20 Feb 2012.)] TJ ET
BT 26.250 356.048 Td /F1 9.8 Tf  [(77.)] TJ ET
BT 43.553 356.048 Td /F1 9.8 Tf  [(Hall AE, Burton H. Legal and ethical implications of inherited cardiac disease in clinical practice within the UK. J Med Ethics. )] TJ ET
BT 26.250 344.143 Td /F1 9.8 Tf  [(2010 Dec;36\(12\):762-6. PubMed PMID: 21112937.)] TJ ET
BT 26.250 324.738 Td /F1 9.8 Tf  [(78.)] TJ ET
BT 43.553 324.738 Td /F1 9.8 Tf  [(Liebman J. Some legal, social, and ethical issues related to the genetic testing revolution, as exemplified in the long QT )] TJ ET
BT 26.250 312.834 Td /F1 9.8 Tf  [(syndrome. J Electrocardiol. 2001;34 Suppl:183-8. PubMed PMID: 11781954.)] TJ ET
BT 26.250 293.429 Td /F1 9.8 Tf  [(79.)] TJ ET
BT 43.553 293.429 Td /F1 9.8 Tf  [(Wren C. Screening children with a family history of sudden cardiac death. Heart. 2006 Jul;92\(7\):1001-6. Review. PubMed )] TJ ET
BT 26.250 281.524 Td /F1 9.8 Tf  [(PMID: 16775115; PubMed Central PMCID: PMC1860723.)] TJ ET
BT 26.250 262.119 Td /F1 9.8 Tf  [(80.)] TJ ET
BT 43.553 262.119 Td /F1 9.8 Tf  [(Schwartz PJ, Spazzolini C, Priori SG, Crotti L, Vicentini A, Landolina M, Gasparini M, Wilde AA, Knops RE, Denjoy I, )] TJ ET
BT 26.250 250.215 Td /F1 9.8 Tf  [(Toivonen L, M�nnig G, Al-Fayyadh M, Jordaens L, Borggrefe M, Holmgren C, Brugada P, De Roy L, Hohnloser SH, Brink PA. )] TJ ET
BT 26.250 238.310 Td /F1 9.8 Tf  [(Who are the long-QT syndrome patients who receive an implantable cardioverter-defibrillator and what happens to them?: data )] TJ ET
BT 26.250 226.405 Td /F1 9.8 Tf  [(from the European Long-QT Syndrome Implantable Cardioverter-Defibrillator \(LQTS ICD\) Registry. Circulation. 2010 Sep )] TJ ET
BT 26.250 214.500 Td /F1 9.8 Tf  [(28;122\(13\):1272-82. Epub 2010 Sep 13. PubMed PMID: 20837891.)] TJ ET
Q
q
15.000 197.120 577.500 579.880 re W n
0.271 0.267 0.267 rg
BT 26.250 759.976 Td /F1 9.8 Tf  [(66.)] TJ ET
BT 43.553 759.976 Td /F1 9.8 Tf  [(Vincent GM. Genotyping has a minor role in selecting therapy for congenital long-QT syndromes at present. Circ Arrhythm )] TJ ET
BT 26.250 748.071 Td /F1 9.8 Tf  [(Electrophysiol. 2008 Aug;1\(3\):227-33; discussion 233. Review. PubMed PMID: 19808413.)] TJ ET
BT 26.250 728.667 Td /F1 9.8 Tf  [(67.)] TJ ET
BT 43.553 728.667 Td /F1 9.8 Tf  [(Moss AJ, Windle JR, Hall WJ, Zareba W, Robinson JL, McNitt S, Severski P, Rosero S, Daubert JP, Qi M, Cieciorka M, )] TJ ET
BT 26.250 716.762 Td /F1 9.8 Tf  [(Manalan AS. Safety and efficacy of flecainide in subjects with Long QT-3 syndrome \(DeltaKPQ mutation\): a randomized, double-)] TJ ET
BT 26.250 704.857 Td /F1 9.8 Tf  [(blind, placebo-controlled clinical trial. Ann Noninvasive Electrocardiol. 2005 Oct;10\(4 Suppl\):59-66. PubMed PMID: 16274417.)] TJ ET
BT 26.250 685.452 Td /F1 9.8 Tf  [(68.)] TJ ET
BT 43.553 685.452 Td /F1 9.8 Tf  [(Ruan Y, Liu N, Bloise R, Napolitano C, Priori SG. Gating properties of SCN5A mutations and the response to mexiletine in )] TJ ET
BT 26.250 673.548 Td /F1 9.8 Tf  [(long-QT syndrome type 3 patients. Circulation. 2007 Sep 4;116\(10\):1137-44. Epub 2007 Aug 13. PubMed PMID: 17698727.)] TJ ET
BT 26.250 654.143 Td /F1 9.8 Tf  [(69.)] TJ ET
BT 43.553 654.143 Td /F1 9.8 Tf  [(Etheridge SP, Sanatani S, Cohen MI, Albaro CA, Saarel EV, Bradley DJ. Long QT syndrome in children in the era of )] TJ ET
BT 26.250 642.238 Td /F1 9.8 Tf  [(implantable defibrillators. J Am Coll Cardiol. 2007 Oct 2;50\(14\):1335-40. Epub 2007 Sep 17. PubMed PMID: 17903632.)] TJ ET
BT 26.250 622.833 Td /F1 9.8 Tf  [(70.)] TJ ET
BT 43.553 622.833 Td /F1 9.8 Tf  [(Pott C, Dechering DG, Reinke F, Muszynski A, Zellerhoff S, Bittner A, K�be J, Wasmer K, Schulze-Bahr E, M�nnig G, )] TJ ET
BT 26.250 610.929 Td /F1 9.8 Tf  [(Kotthoff S, Eckardt L. Successful treatment of catecholaminergic polymorphic ventricular tachycardia with flecainide: a case )] TJ ET
BT 26.250 599.024 Td /F1 9.8 Tf  [(report and review of the current literature. Europace. 2011 Jun;13\(6\):897-901. Epub 2011 Feb 2. Review. PubMed PMID: )] TJ ET
BT 26.250 587.119 Td /F1 9.8 Tf  [(21292648.)] TJ ET
BT 26.250 567.714 Td /F1 9.8 Tf  [(71.)] TJ ET
BT 43.553 567.714 Td /F1 9.8 Tf  [(Wilde AA, Pinto YM. Cost-effectiveness of genotyping in inherited arrhythmia syndromes: are we getting value for the )] TJ ET
BT 26.250 555.810 Td /F1 9.8 Tf  [(money? Circ Arrhythm Electrophysiol. 2009 Feb;2\(1\):1-3. PubMed PMID: 19808437.)] TJ ET
BT 26.250 536.405 Td /F1 9.8 Tf  [(72.)] TJ ET
BT 43.553 536.405 Td /F1 9.8 Tf  [(Van Langen IM, Birnie E, Alders M, Jongbloed RJ, Le Marec H, Wilde AA. The use of genotype-phenotype correlations in )] TJ ET
BT 26.250 524.500 Td /F1 9.8 Tf  [(mutation analysis for the long QT syndrome. J Med Genet. 2003 Feb;40\(2\):141-5. PubMed PMID: 12566525; PubMed Central )] TJ ET
BT 26.250 512.595 Td /F1 9.8 Tf  [(PMCID: PMC1735373.)] TJ ET
BT 26.250 493.191 Td /F1 9.8 Tf  [(73.)] TJ ET
BT 43.553 493.191 Td /F1 9.8 Tf  [(Phillips KA, Ackerman MJ, Sakowski J, Berul CI. Cost-effectiveness analysis of genetic testing for familial long QT )] TJ ET
BT 26.250 481.286 Td /F1 9.8 Tf  [(syndrome in symptomatic index cases. Heart Rhythm. 2005 Dec;2\(12\):1294-300. PubMed PMID: 16360080.)] TJ ET
BT 26.250 461.881 Td /F1 9.8 Tf  [(74.)] TJ ET
BT 43.553 461.881 Td /F1 9.8 Tf  [(Kaufman ES. Efficient genotyping for congenital long QT syndrome. JAMA. 2005 Dec 21;294\(23\):3027-8. PubMed PMID: )] TJ ET
BT 26.250 449.976 Td /F1 9.8 Tf  [(16414952.)] TJ ET
BT 26.250 430.572 Td /F1 9.8 Tf  [(75.)] TJ ET
BT 43.553 430.572 Td /F1 9.8 Tf  [(Perez MV, Kumarasamy NA, Owens DK, Wang PJ, Hlatky MA. Cost-effectiveness of genetic testing in family members of )] TJ ET
BT 26.250 418.667 Td /F1 9.8 Tf  [(patients with long-QT syndrome. Circ Cardiovasc Qual Outcomes. 2011 Jan 1;4\(1\):76-84. Epub 2010 Dec 7. PubMed PMID: )] TJ ET
BT 26.250 406.762 Td /F1 9.8 Tf  [(21139095.)] TJ ET
BT 26.250 387.357 Td /F1 9.8 Tf  [(76.)] TJ ET
BT 43.553 387.357 Td /F1 9.8 Tf  [(Medica. Genetic testing for cardiac channelopathies: utilization management policy \(number III-DIA.05\). Available at: )] TJ ET
BT 26.250 375.453 Td /F1 9.8 Tf  [(https://provider.medica.com/C10/PolicyUtilization/Document%20Library/IIIDIA05.pdf. Accessed 20 Feb 2012.)] TJ ET
BT 26.250 356.048 Td /F1 9.8 Tf  [(77.)] TJ ET
BT 43.553 356.048 Td /F1 9.8 Tf  [(Hall AE, Burton H. Legal and ethical implications of inherited cardiac disease in clinical practice within the UK. J Med Ethics. )] TJ ET
BT 26.250 344.143 Td /F1 9.8 Tf  [(2010 Dec;36\(12\):762-6. PubMed PMID: 21112937.)] TJ ET
BT 26.250 324.738 Td /F1 9.8 Tf  [(78.)] TJ ET
BT 43.553 324.738 Td /F1 9.8 Tf  [(Liebman J. Some legal, social, and ethical issues related to the genetic testing revolution, as exemplified in the long QT )] TJ ET
BT 26.250 312.834 Td /F1 9.8 Tf  [(syndrome. J Electrocardiol. 2001;34 Suppl:183-8. PubMed PMID: 11781954.)] TJ ET
BT 26.250 293.429 Td /F1 9.8 Tf  [(79.)] TJ ET
BT 43.553 293.429 Td /F1 9.8 Tf  [(Wren C. Screening children with a family history of sudden cardiac death. Heart. 2006 Jul;92\(7\):1001-6. Review. PubMed )] TJ ET
BT 26.250 281.524 Td /F1 9.8 Tf  [(PMID: 16775115; PubMed Central PMCID: PMC1860723.)] TJ ET
BT 26.250 262.119 Td /F1 9.8 Tf  [(80.)] TJ ET
BT 43.553 262.119 Td /F1 9.8 Tf  [(Schwartz PJ, Spazzolini C, Priori SG, Crotti L, Vicentini A, Landolina M, Gasparini M, Wilde AA, Knops RE, Denjoy I, )] TJ ET
BT 26.250 250.215 Td /F1 9.8 Tf  [(Toivonen L, M�nnig G, Al-Fayyadh M, Jordaens L, Borggrefe M, Holmgren C, Brugada P, De Roy L, Hohnloser SH, Brink PA. )] TJ ET
BT 26.250 238.310 Td /F1 9.8 Tf  [(Who are the long-QT syndrome patients who receive an implantable cardioverter-defibrillator and what happens to them?: data )] TJ ET
BT 26.250 226.405 Td /F1 9.8 Tf  [(from the European Long-QT Syndrome Implantable Cardioverter-Defibrillator \(LQTS ICD\) Registry. Circulation. 2010 Sep )] TJ ET
BT 26.250 214.500 Td /F1 9.8 Tf  [(28;122\(13\):1272-82. Epub 2010 Sep 13. PubMed PMID: 20837891.)] TJ ET
Q
q
0.000 0.000 0.000 rg
BT 291.710 19.825 Td /F1 11.0 Tf  [(10)] TJ ET
BT 25.000 19.825 Td /F1 11.0 Tf  [(PLOS Currents Evidence on Genomic Tests)] TJ ET

Q
endstream
endobj
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