Genetic testing for long QT syndrome and the category of cardiac ion channelopathies

·
Citation
PDF, XML
Authors

Abstract

Cardiac ion channel mutational analysis is a category of genetic testing used in clinical practice for determining the status of long QT syndrome, short QT syndrome, catecholaminergic polymorphic ventricular tachycardia, and Brugada syndrome genes in blood, saliva, or tissue from patients and family members at risk for cardiac events such as syncope and sudden death. Such testing is most informative following careful phenotypic characterization. Individuals with ion channelopathies may benefit from prevention (avoidance of triggers and predisposing drugs) and treatment (e.g., beta blocker therapy, implantable cardioverter-defibrillator (ICD) placement) modalities.

Funding Statement

Funding for this project was made possible by the National Office of Public Health Genomics, Centers for Disease Control and Prevention through McKing Consulting Corporation, contract # 200-2009-F-32675.

Clinical Scenario

In patients with fainting (especially occurring during physical exertion or emotional/auditory arousal), seizures, a history of aborted cardiac arrest, a family history of sudden death, or who have themselves succumbed to sudden cardiac death (SCD), cardiac ion channel mutation testing, typically in conjunction with electrocardiography, can provide important information. Performed with cardiac evaluation, genetic testing may be used to determine the status of long QT syndrome (LQTS), short QT syndrome (SQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and Brugada syndrome (BrS) genes from blood, saliva, or tissue specimens, including postmortem samples123. While these conditions demonstrate characteristic electrocardiographic patterns (LQTS – a prolonged QT interval on resting ECG (part of the Schwartz-Moss diagnostic score)4; CPVT – ventricular ectopy5; BrS – ST segment elevation2), these findings may be absent or inconclusive on a single clinical test. Similarly, post-mortem samples may be accompanied by insufficient clinical data for diagnostic classification. Genetic testing has been used to exclude one condition over another and to provide definitive diagnosis in many such situations167. For the patient whose symptoms, ECG, and/or other adjunctive tests58 have led to a clinical diagnosis, the test can identify pertinent risks and assist management. In addition, relatives of affected patients, who may have no symptoms but are capable of passing on an abnormal gene, can be identified through techniques like cascade screening1369. Therapies for patients displaying mutations include avoidance of physical triggers and aggravating drugs, placement on anti-arrhythmic drug or beta blocker therapy10111213, use of mechanical devices (pacemakers, ICDs)2, and sympathectomy surgery4.

Test Description

Cardiac ion channelopathies result from adverse alterations in genes that code for protein subunits of cardiac ion channels1. The literature differentiates these channelopathies in terms of their subtypes (e.g., for long QT syndrome, LQT1, LQT2, LQT3, LQT4, LQT5, LQT6, …, LQT13) and the name of the gene affected (KCNQ1 for LQT1; KCNH2 for LQT2; SCN5A for LQT3; ANK2 for LQT4; KCNE1 for LQT5; KCNE2 for LQT6, …, KCNJ5 for LQT13). Genetic testing is available through a number of commercial and university-based genetic diagnostics laboratories1141516. Transgenomic (formerly PGx Health and Genaissance), GeneDx, and Correlagen all offer genetic assays allowing genotyping of LQTS, SQTS, CPVT, and BrS. For example, panels offered by Transgenomic17 and GeneDx18 test for 13 and 12 LQTS genes, respectively, KCNQ1, KCNH2, andSCN5A (LQT1-3) mutations being most frequent; 3 SQTS genes – mutations in the KCNH2, KCNQ1, andKCNJ2 genes; 4 (Transgenomic) and 2 (GeneDx) CPVT genes, RYR2 mutations being most frequent; and 7 BrS genes, SCN5A mutations being most frequent. The Masonic Medical Research Laboratory covers these conditions for research purposes, but specializes in acquired as opposed to congenital long QT syndrome19. Samples are collected in an EDTA-containing tube; the DNA is isolated from fresh whole blood. DNA amplification by polymerase chain reaction (PCR) is then used to generate templates for direct sequencing. DNA, frozen blood, saliva, and other tissue samples such as buccal specimens have recently been accommodated by some labs1718. Detailed results are provided for each test panel, typically with a description of known literature on any identified mutation and its likelihood to cause disease. Focused testing for a single mutation relevant to a patient’s family, rather than a panel of potentially involved genes, is available at a lower cost.

Public Health Importance

The public health importance of these inherited arrhythmia syndromes is highlighted by their potential lethality, mostly due to ventricular tachyarrhythmias20. Long QT syndrome may be responsible for as many as 3,000 unexpected deaths in children and young adults annually in the United States21. Catecholaminergic polymorphic ventricular tachycardia carries a high mortality in untreated cases57. The current state of technology, however, does not enable arrhythmia screening of broad, potentially at-risk populations – athletes, all children, all patients exposed to QT-prolonging drugs, or all patients with a history of syncope616. Subpopulations of sudden death victims are of great interest. It is estimated that approximately 25-35% of autopsy-negative or unexplained sudden cardiac death in the young, and 10% of sudden infant death (SIDS) may be attributable to mutations in either LQTS or CPVT susceptibility genes22. Brugada syndrome may be responsible for 4-15% of unexpected sudden deaths, particularly in individuals with an apparently normal heart232425.

Table of Cardiac Ion Channelopathies
Long QT syndrome (LQTS) 1726272875 Short QT syndrome (SQTS) 171829 Catecholaminergic polymorphic ventricular tachycardia (CPVT) 5173031 Brugada syndrome (BrS) 1732333435
Prevalence 1:5,000 to 1:2,000 Rare – fewer than 30 cases published 1:7,000 to 1:10,000 1:800 (Japan); 1:6,000 (U.S. & Europe) type 1 ECG pattern
Annual mortality rate 0.3% (LQT1)
0.6% (LQT2)
0.56% (LQT3)
Unidentified 3.1% 4% (pts. with type 1 ECG pattern)
Mean age of first event 14 ± 12 yrs. 40 ± 24 yrs. 15 ± 10 yrs. 42 ± 16 yrs. (pts. with type 1 ECG)
Diagnostic Yield – Genetic Testing 75-80% 15-20% 65-75% 11-40% (see Clinical Validity)

In the case of LQTS, the specific genotype has prognostic value16. In studies ranging from 250 to 300,000 genotyped individuals through age 60 drawn from the International LQTS Registry, the LQT3 genotype has demonstrated a 5- to 8-fold higher risk for life-threatening events compared to the LQT1 and 2 genotypes36. The LQT2 genotype displays a risk intermediate between LQT1 and LQT336, though the statistical strength and ordering of this relationship depends on age, sex, and source of the cohort1037. Subgroup analyses have more precisely defined the impact of QTc duration and genotype in children and adolescents with LQT1 and 238.

Published Reviews, Recommendations and Guidelines

Systematic evidence reviews

The Hayes Inc. Genetic Test Evaluation (GTE) Program has prepared three evaluations of ion channelopathies: long QT syndrome, CPVT, and Brugada syndrome. These reviews were based on studies of primary literature retrieved from PUBMED and Embase in the following date ranges: LQTS – January 1, 1996 to June 16, 2009; CPVT – January 1, 1996 to February 10, 2010; and Brugada syndrome – January 1, 1996 to August 3, 201039. DNA Direct, Inc. has published two systematic reviews of LQTS genetic testing through its Genomic Medicine Institute. The reviews, which the company makes available with interactive tools and decision support, are based on studies of primary patient data published between 2001 and 200840. BlueCross BlueShield Association and Kaiser Permanente published a systematic review of genetic testing for long QT syndrome through the BlueCross BlueShield Technology Evaluation Center (BCBS Tec)41. The review was based on studies of primary patient data appearing in Medline and PUBMED published between 1990 and October 2007. The Australia and New Zealand Horizon Scanning Network released a Horizon Scanning Report on genetic testing for congenital long QT syndrome based principally on nine peer-reviewed articles, and detailing safety (e.g., false negatives), effectiveness, clinical utility (cost-effectiveness), and ethical (consent and privacy, harms from testing, access) considerations42. Investigative teams have published comprehensive clinical-epidemiologic reviews of both long QT syndrome as a family and several of the other channelopathies under Human Genome Epidemiology (HuGE) reviews (e.g., long QT syndrome21) and GeneReviews (e.g., Brugada syndrome43).

Recommendations by independent groups

Two independent reviews have concluded that genetic testing has diagnostic value, including for the identification of asymptomatic heterozygotes, for all four syndromes; definitive prognostic value for LQTS and weak or contingent prognostic value (depending on the nature of the findings) for CPVT and BrS; and practical value in the determination of therapy for LQTS alone130. One of the teams also published an “evidence-based” genetic testing scoring system to compare the relative clinical value of genetic testing over these conditions (LQTS > CPVT > BrS > SQTS)44. SQTS’s low score is associated with paucity of data, this condition having first been described in 200015. Criteria on when to screen for each channelopathy, based on consensus documents and primary literature from 1995 onward, are laid out by Tzou and Gerstenfeld15. This review concluded that genetic testing can lead to genotype-specific therapy in the case of LQTS, and decisions about ICD placement for malignant arrhythmias associated with CPVT and SQTS15.

Guidelines by independent groups

A 2007 consensus report by the U.S. National Heart, Lung, and Blood Institute and the Office of Rare Diseases on gene mutations affecting ion channel function concluded that genetic testing for LQTS must be combined with clinical evaluation, and noted lack of clarity in the proportion of SQTS cases that might be explained by the corresponding KCNH2, KCNJ2, and KCNQ1 genes45. A 2011 Heart Rhythm Society (HRS) / European Heart Rhythm Association (EHRA) consensus statement further states that LQTS genetic testing is recommended for any asymptomatic patient with idiopathic (not attributable to QT prolonging disease states or conditions) QTc values > .48 s. (prepuberty) or > .50 s. (adult), and may be considered for QTc values >= .46 and .48, respectively6. (QTc = “heart rate-corrected QT interval,” as per the Bazett formula4.) The Heart Rhythm UK Familial Sudden Death Syndromes Statement Development Group published in 2008 a position statement on genetic testing for sudden cardiac death syndromes based on a comprehensive review of English language publications, grading of the evidence, and secondary review of the evidence by an external committee3. The Group followed with a position statement on ICD placement for these conditions based on risk of SCD46. The first position statement and the more recent HRS/EHRA report recommend genetic testing for all patients with a firm diagnosis of congenital LQTS and those with clinical features of CPVT (due to its severity, despite an acknowledged lower clinical sensitivity), but that expert clinical and family history assessment are needed when genetic testing is undertaken for borderline LQTS cases and known or suspected cases of BrS. Practice guidelines from the American College of Cardiology / American Heart Association / European Society of Cardiology47 have noted an evolving role for genetic testing of LQTS in risk stratification and clinical decision making. Both independent reviews and professional society guidelines agree that genetic testing by itself is not recommended in making a diagnosis or prognosis for BrS, though it may be used to support clinical diagnosis, and early detection of at-risk relatives62548. Several HRS / EHRA consensus statements clarify that genetic testing can be useful in patients clinically suspected of having BrS with a type 1 (“coved” ST segment elevation) ECG pattern, but that it is not indicated in the setting of an isolated type 2 (less specific, “saddleback” ST elevation) or 3 (either shape but less pronounced elevation) pattern62025.

Evidence Overview

Analytic Validity:

Commercially available channelopathy genetic testing (CGT) for LQTS, SQTS, CPVT, and BrS involves direct sequencing of protein-coding portions and flanking regions of targeted exons following PCR amplification. Sequencing is performed in both forward and reverse directions. Sequences are analyzed for heterozygous and homozygous variants using public reference sequences1741. For the FAMILION® test, variants detected in the initial analysis are confirmed by repeating the sequencing twice in the forward and three times in the backward direction. Transgenomic reports a CGT error rate of < 1% 17. GeneDx indicates a 98% “technical sensitivity” for assessment of each of the four conditions18. The John Welsh Cardiovascular Laboratory at Baylor College of Medicine makes available genetic diagnostic testing using DNA sequencing analysis for KCNJ2 (LQT7) and CAV3 (LQT9) mutations. This facility reports approximately 99% detection of the exons that are sequenced49. Failure to detect variants in the laboratory setting is attributed to refractoriness of the amplicon to analysis by direct DNA sequencing or real-time PCR detection, sample mishandling, sample tracking errors, errors in data analysis, and other gene specific issues (see Clinical Validity)17. The FAMILION® analytic specificity approaches 100% for “Class I” (deleterious or probably deleterious) mutations, and approximates 95% for “Class II” mutations (of uncertain clinical significance – possibly deleterious)41.

Clinical Validity:

The near perfect analytic sensitivities of these assays must be contrasted with the ability to detect genetic variants in the clinical setting. The yield for the first 2,500 consecutive unrelated cases referred by physicians for commercially available long QT syndrome genetic testing (low-, intermediate-, and high-pretest probability) was 36%; values in the literature range between 33 and 39%50. Tester et al. reported greater yields of 72 to 78% using the 5 major LQTS genes for patients with the highest clinical probability for LQTS (Schwartz-Moss score >= 4 4)37. Transgenomic reports a 75 to 80% yield for such patients based upon multiple data sets1751. False negatives may be explained by a number of factors, including the existence of private mutations37, the presence of non-targeted exons17 and relevant introns outside tested splice sites16, and the existence of large deletion and duplication mutations (generally on the scale of a whole exon or more)717. LQTS is in the upper range among cardiac conditions in terms of number of affected genes (13) and allelic mutations (>800) while BrS lies in the midrange (8 genes and >400 allelic mutations). By comparison, current compendia of arrhythmogenic right ventricular dysplasia/cardiomyopathy list 9 affected genes and >400 allelic mutations, while Marfan syndrome has ~600 allelic mutations in the FBN1 fibrillin gene.

Authors have reported various mutational hotspots in the case of LQTS arising either independently or due to founder effects, which because of their severity may aid risk stratification21. Interpretation of results for probands and family members is complicated by variable penetrance in family members with the same genotype52, and the possibility of compound mutations, observed in 4 to 10% of mutation positive individuals37505354. Estimated positive predictive values (EPV – percent of mutations found in definite cases that would cause the condition) for LQTS genetic testing based on an assessment of > 1300 unrelated index cases with Schwartz score >= 4 or QTc >= .48 s. are: 96% (95% C.I., 94-98) for KCNQ1; 93% (89-95) for KCNH2; and 63% (40-77) for SCN5A55. Nonmissense mutations have an EPV > 99% regardless of location55. EPVs for missense mutations range from 0% in the interdomain linker of SCN5A to 100% in the transmembrane/linker/pore regions of KCNH2. Similar figures are lacking for the other channelopathies.

Several groups have investigated ECG genotyping (to be distinguished from use in initial diagnosis) through T-wave morphology as a means of reducing the cost of LQTS mutational genotyping565758. Sensitivity is highly dependent on the gene being assessed, and varies between 92% (LQT2) and 47% (LQT3)5758. QTc interval alone lacks predictive value for genotyping5657.

For channelopathy genetic testing (CGT) of the other inherited arrhythmia syndromes, Transgenomic reports a clinical sensitivity of 65-75% (CPVT), 25-40% (BrS), and 15-20% (SQTS)17. GeneDx18 and the Correlagen CardioGeneScan®59 also test for these conditions. The GeneDx and Correlagen test information / FAQ sheets provide rough estimates of clinical sensitivity; figures from Correlagen are also reported with the assays. Some commercial laboratories only provide CPVT screening of a limited number of select exons encompassing critical RYR2 regions, which can contribute to false negatives30. Disagreement exists on the impact of combining other variables with mutational results in order to increase clinical sensitivity; results vary by arrhythmia syndrome, genotype, and size of the study population102760.

Mutational analysis of 27 SCN5A exons on cases from BrS databases at 9 international centers resulted in yields of 11-28%3543, lower than the 25-40% figure Transgenomic reports174360. The literature suggests that for BrS about a quarter of the patients or fewer carry an SCN5A mutation (commercial assays also include other lower frequency mutations)1225. The low clinical sensitivity of genetic testing for Brugada syndrome, due to the low gene frequency for the most prevalent type of mutation (involving SCN5A), incompleteness of known allelic variants, and the role of an organic substrate in many cases, limits its diagnostic capability156162. Genetic testing for BrS is more often used for confirmatory purposes1. Higher yields for the various channelopathies accrue in families with at least one recorded case of sudden unexpected death, permitting detection of potentially affected relatives24.

Clinical Utility:

Genetic analysis has been found useful in risk stratification of LQTS patients and detection of at-risk family members, though current knowledge of CPVT genetic variants does not in itself does not yield prognostic information15222730364148. “Intragenic risk stratification” based on mutation type and location, and cellular function, particularly for the LQT1 and 2 genotypes, has been an increasing part of large scale studies but is not yet in widespread practice1611414763. A meta-analysis of 30 Brugada syndrome prospective studies by Gehi et al.64 concluded family history of SCD and presence of an SCN5A mutation by themselves are insufficient to predict risk for cardiac events in BrS. Instead, debates about risk stratification for patients with this condition have taken place largely on the electrocardiographic front65. The presence of spontaneous ST-segment elevation, particularly with a type-1 pattern, in conjunction with a history of syncope remains the strongest predictor of BrS risk2.

Mutational information can serve as an adjunct to clinical and phenotypic assessment of genotype in therapeutic decisions for LQTS303648, though this role is not without controversy1012164166. Clear evidence exists for genotype-specific therapy in management of the LQT1, 2, and 3 genotypes, but it is less substantiated for the other LQTS genotypes due to their rarity111213366768. Disagreement exists on the use of intragenic, site-specific information to predict actual clinical phenotype or response to therapy for the LQTS genotypes1137. In analyzing retrospective data on 27 of 128 LQTS patients in the 3 to 13 year-old age range who received either pacemakers or ICDs as therapy, investigators in a 3-area study (Utah, British Columbia, and Arizona) found no association between device placement decisions and implementation of genetic testing. However, the authors also noted that all patients with SCN5A (LQT3) mutations had therapeutic devices, though only 1 of 30 with a KCNQ1 (LQT1) mutation had one69. The use of genetic testing in therapeutic decision making for the other inherited arrhythmia syndromes is not yet substantiated but appears promising16304870. ECG remains the principal tool for BrS diagnosis and therapeutic follow-up21625.

Several teams have evaluated step-wise or tiered strategies also including phenotypic assessment to increase the efficiency of LQTS and CPVT genetic testing17537172. Targeted screening based on phenotypic information can lower the cost of more comprehensive LQTS genetic testing by ~60% 71. Phillips et al. found LQTS genetic testing more cost-effective than not testing 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 as a standard threshold)7374. Bai et al., in looking at 546 patients referred to a large consortium of LQTS research laboratories, found the highest yield (64%) and lowest cost ($8,418 per positive genotyping) for patients with ECG-confirmed LQTS, but diminishing yields and increasing costs for patients with borderline QTc intervals and those with normal intervals but a positive family history for SCD60. They recommended genetic testing be prioritized to those with a “conclusive diagnosis” of LQTS. Genotyping of individuals with a conclusive diagnosis of CPVT, and of patients with type 1 BrS ECG with atrioventricular block was also found to be cost-effective. Apart from this report, the host of cost-effectiveness analyses for Brugada syndrome deal with the issue of implantation of ICDs.

Perez et al. used a Markov model to assess the cost-effectiveness of different strategies for testing then treating an asymptomatic 10 year-old first degree relative of a patient with clinically evident LQTS75. They concluded that genetic testing is moderately expensive, at $67,400 per quality adjusted life year saved, but improves with higher clinical suspicion of the proband, number of relatives tested, and stronger family history of sudden death.

CGT is covered to different extents by insurance providers, ranging from denial to 100% coverage, with most covering at least 50 to 75% of the cost22. Some health plan policies explicitly limit genetic test reimbursement to LQTS while excluding the other channelopathies76.

Public Health Ethical, Legal, and Social (PHELSI) Considerations:

Genetic testing for cardiac channelopathies is laden with ethical issues, including the search for a balance between individual privacy vs. alerting at-risk family members, as well as psychosocial issues inherent in informing individuals of their risk17778. A review by Wren provides general recommendations for genetic testing of children in families with a history of SCD, and offers ethical considerations in childhood genetic testing for Brugada syndrome79. Use of pacemakers and ICDs in children, while often done under situations of medical necessity, can involve trade-offs between benefit and adverse effects456980. Screening for LQTS mutations in particular racial-ethnic groups deserves further ethical analysis21. Personalization of drug treatment through determination of individually specific genotype remains a hoped-for future direction in the field175. Risk assessment for inherited heart arrhythmias is also becoming a part of direct-to-consumer genetic testing, an area subject to increasing attention by policy makers.

Links

The commercial and university-based laboratories cited above are approved under the Clinical Laboratory Improvement Amendments (CLIA). Several, but not all, are accredited by the College of American Pathologists (CAP). These assays are developed and validated in-house, thus do not require FDA approval.

Relevant web sites:

  • IRCCS Fondazione Salvatore Maugeri Molecular Cardiology Laboratories. Gene Connection for the Heart Inherited Arrhythmias Database. www.fsm.it/cardmoc. Up-to-date compendium of inherited arrhythmia syndrome (cardiac ion channelopathy, arrhythmogenic right ventricular cardiomyopathy, and others) mutations and polymorphisms, and condition synopses.
  • Heart Rhythm Society. www.hrsonline.org. International society concerned with education and advocacy for cardiac arrhythmia professionals and patients. Web site describes and provides access to professional educational programs, clinical guidelines and consensus statements relating to diagnosis and management, and relevant legislation.
  • Cardiac Arrhythmias Research and Education (CARE) Foundation. www.longqt.com. Advocacy and awareness-raising organization aimed at preventing sudden cardiac death due to acquired and heritable heart rhythm disorders. Web site reports professional educational resources, and details emerging advocacy issues, support groups, and genetic testing laboratories.
  • Sudden Arrhythmia Death Syndromes Foundation. www.sads.org. Aimed at preventing sudden and unexpected cardiac death in children and young adults, the Foundation’s web site describes public awareness-raising activities, advocacy initiatives impacting patients and professionals, and patient and family support services.
  • Drugs that Prolong the QT Interval and/or Induce Torsades de Pointes Ventricular Arrhythmia. www.qtdrugs.org. Web site provides a comprehensive list of arrhythmogenic drugs to be avoided by LQTS patients, lists drugs by risk group, provides consumer education tools, and describes the drug-induced arrhythmias case registry.
  • Raymond Brugada Senior Foundation, www.brugada.org. Foundation web site provides a full description of Brugada syndrome, cites relevant literature and professional policies, and offers avenues for partnering in research and joining a support group.
  • BrugadaDrugs.org. www.brugadadrugs.org. Web site provides a comprehensive list of arrhythmogenic drugs to be avoided by Brudaga syndrome patients, lists drugs by risk group, cites drugs diagnostic for Brs, and offers a patient letter listing drugs to be avoided.

Competing Interests

The authors have declared that no competing interests exist.

References

  • Tester DJ, Ackerman MJ. Genetic testing for potentially lethal, highly treatable inherited cardiomyopathies/channelopathies in clinical practice. Circulation. 2011 Mar 8;123(9):1021-37. Review. PubMed PMID: 21382904; PubMed Central PMCID: PMC3073829.
  • Benito B, Brugada R, Brugada J, Brugada P. Brugada syndrome. Prog Cardiovasc Dis. 2008 Jul-Aug;51(1):1-22. Review. PubMed PMID: 18634914.
  • Heart Rhythm UK Familial Sudden Death Syndromes Statement Development Group. Clinical indications for genetic testing in familial sudden cardiac death syndromes: an HRUK position statement. Heart. 2008 Apr;94(4):502-7. Epub 2007 Jul 30. PubMed PMID: 17664186.
  • Moss AJ. Long QT Syndrome. JAMA. 2003 Apr 23-30;289(16):2041-4. Review. PubMed PMID: 12709446.
  • Priori SG, Napolitano C, Memmi M, Colombi B, Drago F, Gasparini M, DeSimone L, Coltorti F, Bloise R, Keegan R, Cruz Filho FE, Vignati G, Benatar A, DeLogu A. Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia. Circulation. 2002 Jul 2;106(1):69-74. PubMed PMID: 12093772.
  • Ackerman MJ, Priori SG, Willems S, Berul C, Brugada R, Calkins H, Camm AJ, Ellinor PT, Gollob M, Hamilton R, Hershberger RE, Judge DP, Le Marec H, McKenna WJ, Schulze-Bahr E, Semsarian C, Towbin JA, Watkins H, Wilde A, Wolpert C, Zipes DP. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). Heart Rhythm. 2011 Aug;8(8):1308-39. PubMed PMID: 21787999.
  • Medeiros-Domingo A, Bhuiyan ZA, Tester DJ, Hofman N, Bikker H, van Tintelen JP, Mannens MM, Wilde AA, Ackerman MJ. The RYR2-encoded ryanodine receptor/calcium release channel in patients diagnosed previously with either catecholaminergic polymorphic ventricular tachycardia or genotype negative, exercise-induced long QT syndrome: a comprehensive open reading frame mutational analysis. J Am Coll Cardiol. 2009 Nov 24;54(22):2065-74. PubMed PMID: 19926015; PubMed Central PMCID: PMC2880864.
  • Takenaka K, Ai T, Shimizu W, Kobori A, Ninomiya T, Otani H, Kubota T, Takaki H, Kamakura S, Horie M. Exercise stress test amplifies genotype-phenotype correlation in the LQT1 and LQT2 forms of the long-QT syndrome. Circulation. 2003 Feb 18;107(6):838-44. PubMed PMID: 12591753.
  • Hofman N, Tan HL, Alders M, van Langen IM, Wilde AA. Active cascade screening in primary inherited arrhythmia syndromes: does it lead to prophylactic treatment? J Am Coll Cardiol. 2010 Jun 8;55(23):2570-6. PubMed PMID: 20513597.
  • Goldenberg I, Moss AJ, Peterson DR, McNitt S, Zareba W, Andrews ML, Robinson JL, Locati EH, Ackerman MJ, Benhorin J, Kaufman ES, Napolitano C, Priori SG, Qi M, Schwartz PJ, Towbin JA, Vincent GM, Zhang L. Risk factors for aborted cardiac arrest and sudden cardiac death in children with the congenital long-QT syndrome. Circulation. 2008 Apr 29;117(17):2184-91. Epub 2008 Apr 21. PubMed PMID: 18427136.
  • Moss AJ, Goldenberg I. Importance of Knowing the Genotype and the Specific Mutation When Managing Patients with Long QT Syndrome. Circ Arrhythm Electrophysiol. 2008 Aug;1(3):213-26; discussion 226. Review. PubMed PMID: 19701491; PubMed Central PMCID: PMC2729934.
  • Hobbs JB, Peterson DR, Moss AJ, McNitt S, Zareba W, Goldenberg I, Qi M, Robinson JL, Sauer AJ, Ackerman MJ, Benhorin J, Kaufman ES, Locati EH, Napolitano C, Priori SG, Towbin JA, Vincent GM, Zhang L. Risk of aborted cardiac arrest or sudden cardiac death during adolescence in the long-QT syndrome. JAMA. 2006 Sep 13;296(10):1249-54. PubMed PMID: 16968849.
  • Moss AJ, Zareba W, Hall WJ, Schwartz PJ, Crampton RS, Benhorin J, Vincent GM, Locati EH, Priori SG, Napolitano C, Medina A, Zhang L, Robinson JL, Timothy K, Towbin JA, Andrews ML. Effectiveness and limitations of beta-blocker therapy in congenital long-QT syndrome. Circulation. 2000 Feb 15;101(6):616-23. PubMed PMID: 10673253.
  • National Center for Biotechnology Information (NCBI). Long QT syndrome 1: clinical laboratories. Available at: http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/clinical_disease_id/115871?db=genetests. Accessed 28 Apr 2011.
  • Tzou WS, Gerstenfeld EP. Genetic testing in the management of inherited arrhythmia syndromes. Curr Cardiol Rep. 2009 Sep;11(5):343-51. Review. PubMed PMID: 19709494.
  • Vincent GM, Zhang L. The role of genotyping in diagnosing cardiac channelopathies : progress to date. Mol Diagn. 2005;9(3):105-18. Review. PubMed PMID: 16271012.
  • Transgenomic. FAMILION technical specifications. Available at: http://www.familion.com/familion/pdf/FAMILION%20Tech%20Sheet%20Dec%2011%20482301-06.pdf. Accessed 16 Feb 2012.
  • GeneDx. Cardiology genetics: long QT syndrome (LQTS) and short QT (SQTS) panels. Available at: http://www.genedx.com/ext_upload_files/info_sheet_lqt.pdf and http://www.genedx.com/ext_upload_files/info_sheet_sql.pdf. Accessed 16 Feb 2012.
  • Masonic Medical Research Laboratory. Genetic screening. Available at: www.mmrl.edu/GeneticScreening.asp. Accessed 29 Mar 2011.
  • Lehmann MH, Brugada R. Brugada syndrome: diagnostic pitfalls. J Emerg Med. 2009 Jul;37(1):79-81; author reply 81-2. Epub 2009 Mar 25. PubMed PMID: 19321285.
  • Modell SM, Lehmann MH. The long QT syndrome family of cardiac ion channelopathies: a HuGE review. Genet Med. 2006 Mar;8(3):143-55. Review. PubMed PMID: 16540748.
  • Ackerman MJ. Cardiac causes of sudden unexpected death in children and their relationship to seizures and syncope: genetic testing for cardiac electropathies. Semin Pediatr Neurol. 2005 Mar;12(1):52-8. Review. PubMed PMID: 15929465.
  • Brugada R, Campuzano O, Brugada P, Brugada J, Hong K. Brugada Syndrome . 2005 Mar 31 [updated 2012 Jan 12]. In: Pagon RA, Bird TD, Dolan CR, Stephens K, editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-. Available from http://www.ncbi.nlm.nih.gov/books/NBK1517/ PubMed PMID: 20301690.
  • van der Werf C, Hofman N, Tan HL, van Dessel PF, Alders M, van der Wal AC, van Langen IM, Wilde AA. Diagnostic yield in sudden unexplained death and aborted cardiac arrest in the young: the experience of a tertiary referral center in The Netherlands. Heart Rhythm. 2010 Oct;7(10):1383-9. Epub 2010 May 31. PubMed PMID: 20646679.
  • Antzelevitch C, Brugada P, Borggrefe M, Brugada J, Brugada R, Corrado D, Gussak I, LeMarec H, Nademanee K, Perez Riera AR, Shimizu W, Schulze-Bahr E, Tan H, Wilde A. Brugada syndrome: report of the second consensus conference: endorsed by the Heart Rhythm Society and the European Heart Rhythm Association. Circulation. 2005 Feb 8;111(5):659-70. Epub 2005 Jan 17. Review. Erratum in: Circulation. 2005 Jul 26;112(4):e74. PubMed PMID: 15655131.
  • Schwartz PJ, Stramba-Badiale M, Crotti L, Pedrazzini M, Besana A, Bosi G, Gabbarini F, Goulene K, Insolia R, Mannarino S, Mosca F, Nespoli L, Rimini A, Rosati E, Salice P, Spazzolini C. Prevalence of the congenital long-QT syndrome. Circulation. 2009 Nov 3;120(18):1761-7. Epub 2009 Oct 19. PubMed PMID: 19841298; PubMed Central PMCID: PMC2784143.
  • Priori SG, Schwartz PJ, Napolitano C, Bloise R, Ronchetti E, Grillo M, Vicentini A, Spazzolini C, Nastoli J, Bottelli G, Folli R, Cappelletti D. Risk stratification in the long-QT syndrome. N Engl J Med. 2003 May 8;348(19):1866-74. PubMed PMID: 12736279.
  • Moss AJ, Schwartz PJ, Crampton RS, Tzivoni D, Locati EH, MacCluer J, Hall WJ, Weitkamp L, Vincent GM, Garson A Jr, et al. The long QT syndrome. Prospective longitudinal study of 328 families. Circulation. 1991 Sep;84(3):1136-44. PubMed PMID: 1884444.
  • Schimpf R, Wolpert C, Gaita F, Giustetto C, Borggrefe M. Short QT syndrome. Cardiovasc Res. 2005 Aug 15;67(3):357-66. Review. PubMed PMID: 15890322.
  • Fowler SJ, Napolitano C, Priori SG. When is genetic testing useful in patients suspected to have inherited cardiac arrhythmias? Curr Opin Cardiol. 2010 Jan;25(1):37-45. Review. PubMed PMID: 19864943.
  • Garratt CJ, Elliott P, Behr E, Camm AJ, Cowan C, Cruickshank S, Grace A, Griffith MJ, Jolly A, Lambiase P, McKeown P, O'Callagan P, Stuart G, Watkins H; Heart Rhythm UK Familial Sudden Cardiac Death Syndromes Statement Development Group. Heart Rhythm UK position statement on clinical indications for implantable cardioverter defibrillators in adult patients with familial sudden cardiac death syndromes. Europace. 2010 Aug;12(8):1156-75. PubMed PMID: 20663787.
  • Miyasaka Y, Tsuji H, Yamada K, Tokunaga S, Saito D, Imuro Y, Matsumoto N, Iwasaka T. Prevalence and mortality of the Brugada-type electrocardiogram in one city in Japan. J Am Coll Cardiol. 2001 Sep;38(3):771-4. PubMed PMID: 11527631.
  • Gallagher MM, Forleo GB, Behr ER, Magliano G, De Luca L, Morgia V, De Liberato F, Romeo F. Prevalence and significance of Brugada-type ECG in 12,012 apparently healthy European subjects. Int J Cardiol. 2008 Oct 30;130(1):44-8. Epub 2007 Dec 4. PubMed PMID: 18054807.
  • Brugada J, Brugada R, Antzelevitch C, Towbin J, Nademanee K, Brugada P. Long-term follow-up of individuals with the electrocardiographic pattern of right bundle-branch block and ST-segment elevation in precordial leads V1 to V3. Circulation. 2002 Jan 1;105(1):73-8. PubMed PMID: 11772879.
  • Kapplinger JD, Tester DJ, Alders M, Benito B, Berthet M, Brugada J, Brugada P, Fressart V, Guerchicoff A, Harris-Kerr C, Kamakura S, Kyndt F, Koopmann TT, Miyamoto Y, Pfeiffer R, Pollevick GD, Probst V, Zumhagen S, Vatta M, Towbin JA, Shimizu W, Schulze-Bahr E, Antzelevitch C, Salisbury BA, Guicheney P, Wilde AA, Brugada R, Schott JJ, Ackerman MJ. An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing. Heart Rhythm. 2010 Jan;7(1):33-46. Epub 2009 Oct 8. PubMed PMID: 20129283; PubMed Central PMCID: PMC2822446.
  • Goldenberg I, Moss AJ, Bradley J, Polonsky S, Peterson DR, McNitt S, Zareba W, Andrews ML, Robinson JL, Ackerman MJ, Benhorin J, Kaufman ES, Locati EH, Napolitano C, Priori SG, Qi M, Schwartz PJ, Towbin JA, Vincent GM, Zhang L. Long-QT syndrome after age 40. Circulation. 2008 Apr 29;117(17):2192-201. Epub 2008 Apr 21. PubMed PMID: 18427134.
  • Tester DJ, Will ML, Haglund CM, Ackerman MJ. Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing. Heart Rhythm. 2005 May;2(5):507-17. PubMed PMID: 15840476.
  • Liu JF, Jons C, Moss AJ, McNitt S, Peterson DR, Qi M, Zareba W, Robinson JL, Barsheshet A, Ackerman MJ, Benhorin J, Kaufman ES, Locati EH, Napolitano C, Priori SG, Schwartz PJ, Towbin J, Vincent M, Zhang L, Goldenberg I; International Long QT Syndrome Registry. Risk Factors for Recurrent Syncope and Subsequent Fatal or Near-Fatal Events in Children and Adolescents With Long QT Syndrome. J Am Coll Cardiol. 2011 Feb 22;57(8):941-50. Erratum in: J Am Coll Cardiol. 2011 Apr 19;57(16):1717. PubMed PMID: 21329841; PubMed Central PMCID: PMC3052409.
  • Hayes, Inc. Genetic test evaluation reports: Genetic testing for long QT syndrome using the Familion® test (PGxHealthTM)(2009), catecholaminergic polymorphic ventricular tachycardia (2010), and Brugada syndrome (2010). Lansdale, PA: Hayes, Inc. Available at: http://www.hayesinc.com/hayes/products_and_services/knowledge-center. Accessed 4 Apr 2011.
  • DNA Direct, Genomic Medicine Institute. Genetic testing for long QT syndrome. (systematic reviews) San Francisco, CA: DNA Direct. 2008. Available at: http://www.dnadirect.com/dnaweb/products/policy-benefit-support.html. Accessed 14 Apr 2011.
  • Blue Cross Blue Shield Association (BCBSA), Technology Evaluation Center (TEC). Genetic testing for long QT syndrome. 2007 TEC Assessments 2008;22(9). Chicago, IL. Available at: http://www.sads.org/images/stories/bcbstecadvisory.pdf. Accessed 10 Dec 2010.
  • Australia and New Zealand Horizon Scanning Network (ANZHSN). Horizon scanning technology horizon scanning report: genetic testing for congenital long QT syndrome. Canberra, Australia: Australian Government Department of Health and Ageing. May 2007. Available at: http://www.horizonscanning.gov.au/internet/horizon/publishing.nsf/Content/58685F8B48CC9EE7CA2575AD0080F340/$File/Final_Long_QT_HS_Report.pdf. Accessed Dec 10, 2010.
  • Brugada R, Campuzano O, Brugada P, Brugada J, Hong K. Brugada Syndrome . 2005 Mar 31 [updated 2012 Jan 12]. In: Pagon RA, Bird TD, Dolan CR, Stephens K, editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-. Available from http://www.ncbi.nlm.nih.gov/books/NBK1517/ PubMed PMID: 20301690.
  • Priori SG, Napolitano C. Role of genetic analyses in cardiology: part I: mendelian diseases: cardiac channelopathies. Circulation. 2006 Feb 28;113(8):1130-5. Review. PubMed PMID: 16505190.
  • Lehnart SE, Ackerman MJ, Benson DW Jr, Brugada R, Clancy CE, Donahue JK, George AL Jr, Grant AO, Groft SC, January CT, Lathrop DA, Lederer WJ, Makielski JC, Mohler PJ, Moss A, Nerbonne JM, Olson TM, Przywara DA, Towbin JA, Wang LH, Marks AR. Inherited arrhythmias: a National Heart, Lung, and Blood Institute and Office of Rare Diseases workshop consensus report about the diagnosis, phenotyping, molecular mechanisms, and therapeutic approaches for primary cardiomyopathies of gene mutations affecting ion channel function. Circulation. 2007 Nov 13;116(20):2325-45. Erratum in: Circulation. 2008 Aug 19;118(8):e132. PubMed PMID: 17998470.
  • Garratt CJ, Elliott P, Behr E, Camm AJ, Cowan C, Cruickshank S, Grace A, Griffith MJ, Jolly A, Lambiase P, McKeown P, O'Callagan P, Stuart G, Watkins H; Heart Rhythm UK Familial Sudden Cardiac Death Syndromes Statement Development Group. Heart Rhythm UK position statement on clinical indications for implantable cardioverter defibrillators in adult patients with familial sudden cardiac death syndromes. Europace. 2010 Aug;12(8):1156-75. PubMed PMID: 20663787.
  • Zipes DP, Camm AJ, Borggrefe M, Buxton AE, Chaitman B, Fromer M, Gregoratos G, Klein G, Moss AJ, Myerburg RJ, Priori SG, Quinones MA, Roden DM, Silka MJ, Tracy C, Smith SC Jr, Jacobs AK, Adams CD, Antman EM, Anderson JL, Hunt SA, Halperin JL, Nishimura R, Ornato JP, Page RL, Riegel B, Blanc JJ, Budaj A, Dean V, Deckers JW, Despres C, Dickstein K, Lekakis J, McGregor K, Metra M, Morais J, Osterspey A, Tamargo JL, Zamorano JL; American College of Cardiology/American Heart Association Task Force; European Society of Cardiology Committee for Practice Guidelines; European Heart Rhythm Association; Heart Rhythm Society. ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (writing committee to develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation. 2006 Sep 5;114(10):e385-484. Epub 2006 Aug 25. PubMed PMID: 16935995.
  • Priori SG, Cerrone M. Molecular genetics: is it making an impact in the management of inherited arrhythmogenic syndromes? Hellenic J Cardiol. 2005 Mar-Apr;46(2):83-7. PubMed PMID: 15847126.
  • John Welsh Cardiovascular Diagnostic Laboratory, Baylor College of Medicine. KCNJ2 and CAV3 mutation analysis. Available at: http://www.bcm.edu/pediatrics/cardiology. Accessed 10 Mar 2011.
  • Kapplinger JD, Tester DJ, Salisbury BA, Carr JL, Harris-Kerr C, Pollevick GD, Wilde AA, Ackerman MJ. Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test. Heart Rhythm. 2009 Sep;6(9):1297-303. Epub 2009 Jun 23. PubMed PMID: 19716085; PubMed Central PMCID: PMC3049907.
  • Taggart NW, Haglund CM, Tester DJ, Ackerman MJ. Diagnostic miscues in congenital long-QT syndrome. Circulation. 2007 May 22;115(20):2613-20. Epub 2007 May 14. PubMed PMID: 17502575.
  • Kaufman ES, Priori SG, Napolitano C, Schwartz PJ, Iyengar S, Elston RC, Schnell AH, Gorodeski EZ, Rammohan G, Bahhur NO, Connuck D, Verrilli L, Rosenbaum DS, Brown AM. Electrocardiographic prediction of abnormal genotype in congenital long QT syndrome: experience in 101 related family members. J Cardiovasc Electrophysiol. 2001 Apr;12(4):455-61. PubMed PMID: 11332568.
  • Napolitano C, Priori SG, Schwartz PJ, Bloise R, Ronchetti E, Nastoli J, Bottelli G, Cerrone M, Leonardi S. Genetic testing in the long QT syndrome: development and validation of an efficient approach to genotyping in clinical practice. JAMA. 2005 Dec 21;294(23):2975-80. PubMed PMID: 16414944.
  • Wilde AA. Long QT syndrome: a double hit hurts more. Heart Rhythm. 2010 Oct;7(10):1419-20. Epub 2010 Jun 22. PubMed PMID: 20601150.
  • Kapa S, Tester DJ, Salisbury BA, Harris-Kerr C, Pungliya MS, Alders M, Wilde AA, Ackerman MJ. Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants. Circulation. 2009 Nov 3;120(18):1752-60. Epub 2009 Oct 19. PubMed PMID: 19841300; PubMed Central PMCID: PMC3025752.
  • Zareba W. Genotype-specific ECG patterns in long QT syndrome. J Electrocardiol. 2006 Oct;39(4 Suppl):S101-6. Epub 2006 Sep 11. Review. PubMed PMID: 16963070.
  • Couderc JP, McNitt S, Xia J, Zareba W, Moss AJ. Repolarization morphology in adult LQT2 carriers with borderline prolonged QTc interval. Heart Rhythm. 2006 Dec;3(12):1460-6. Epub 2006 Aug 10. PubMed PMID: 17161789.
  • Zhang L, Timothy KW, Vincent GM, Lehmann MH, Fox J, Giuli LC, Shen J, Splawski I, Priori SG, Compton SJ, Yanowitz F, Benhorin J, Moss AJ, Schwartz PJ, Robinson JL, Wang Q, Zareba W, Keating MT, Towbin JA, Napolitano C, Medina A. Spectrum of ST-T-wave patterns and repolarization parameters in congenital long-QT syndrome: ECG findings identify genotypes. Circulation. 2000 Dec 5;102(23):2849-55. PubMed PMID: 11104743.
  • Correlagen. Frequently asked questions about Correlagen’s CardioGeneScan (CGS). Available at: http://www.correlagen.com/fields/cardiology/downloads/CARDIO_CRLGFAQS.pdf. Accessed 16 Mar 2011.
  • Bai R, Napolitano C, Bloise R, Monteforte N, Priori SG. Yield of genetic screening in inherited cardiac channelopathies: how to prioritize access to genetic testing. Circ Arrhythm Electrophysiol. 2009 Feb;2(1):6-15. Epub 2009 Feb 10. PubMed PMID: 19808439.
  • Gross GJ. Management of Brugada syndrome in children. Pediatr Health 2010 Feb;4(1):35-43.
  • Martini B, Cannas S, Nava A. Brugada by any other name? Eur Heart J. 2001 Oct;22(19):1835-6. PubMed PMID: 11549306.
  • Shimizu W, Moss AJ, Wilde AA, Towbin JA, Ackerman MJ, January CT, Tester DJ, Zareba W, Robinson JL, Qi M, Vincent GM, Kaufman ES, Hofman N, Noda T, Kamakura S, Miyamoto Y, Shah S, Amin V, Goldenberg I, Andrews ML, McNitt S. Genotype-phenotype aspects of type 2 long QT syndrome. J Am Coll Cardiol. 2009 Nov 24;54(22):2052-62. PubMed PMID: 19926013; PubMed Central PMCID: PMC2808400.
  • Gehi AK, Duong TD, Metz LD, Gomes JA, Mehta D. Risk stratification of individuals with the Brugada electrocardiogram: a meta-analysis. J Cardiovasc Electrophysiol. 2006 Jun;17(6):577-83. PubMed PMID: 16836701.
  • Nof E, Antzelevitch C. Risk stratification [corrected] of Brugada syndrome revisited. Isr Med Assoc J. 2008 Jun;10(6):462-4. Erratum in: Isr Med Assoc J. 2008 Jul;10(7):549. PubMed PMID: 18669148; PubMed Central PMCID: PMC2562553.
  • Vincent GM. Genotyping has a minor role in selecting therapy for congenital long-QT syndromes at present. Circ Arrhythm Electrophysiol. 2008 Aug;1(3):227-33; discussion 233. Review. PubMed PMID: 19808413.
  • Moss AJ, Windle JR, Hall WJ, Zareba W, Robinson JL, McNitt S, Severski P, Rosero S, Daubert JP, Qi M, Cieciorka M, Manalan AS. Safety and efficacy of flecainide in subjects with Long QT-3 syndrome (DeltaKPQ mutation): a randomized, double-blind, placebo-controlled clinical trial. Ann Noninvasive Electrocardiol. 2005 Oct;10(4 Suppl):59-66. PubMed PMID: 16274417.
  • Ruan Y, Liu N, Bloise R, Napolitano C, Priori SG. Gating properties of SCN5A mutations and the response to mexiletine in long-QT syndrome type 3 patients. Circulation. 2007 Sep 4;116(10):1137-44. Epub 2007 Aug 13. PubMed PMID: 17698727.
  • Etheridge SP, Sanatani S, Cohen MI, Albaro CA, Saarel EV, Bradley DJ. Long QT syndrome in children in the era of implantable defibrillators. J Am Coll Cardiol. 2007 Oct 2;50(14):1335-40. Epub 2007 Sep 17. PubMed PMID: 17903632.
  • Pott C, Dechering DG, Reinke F, Muszynski A, Zellerhoff S, Bittner A, Köbe J, Wasmer K, Schulze-Bahr E, Mönnig G, Kotthoff S, Eckardt L. Successful treatment of catecholaminergic polymorphic ventricular tachycardia with flecainide: a case report and review of the current literature. Europace. 2011 Jun;13(6):897-901. Epub 2011 Feb 2. Review. PubMed PMID: 21292648.
  • Wilde AA, Pinto YM. Cost-effectiveness of genotyping in inherited arrhythmia syndromes: are we getting value for the money? Circ Arrhythm Electrophysiol. 2009 Feb;2(1):1-3. PubMed PMID: 19808437.
  • Van Langen IM, Birnie E, Alders M, Jongbloed RJ, Le Marec H, Wilde AA. The use of genotype-phenotype correlations in mutation analysis for the long QT syndrome. J Med Genet. 2003 Feb;40(2):141-5. PubMed PMID: 12566525; PubMed Central PMCID: PMC1735373.
  • Phillips KA, Ackerman MJ, Sakowski J, Berul CI. Cost-effectiveness analysis of genetic testing for familial long QT syndrome in symptomatic index cases. Heart Rhythm. 2005 Dec;2(12):1294-300. PubMed PMID: 16360080.
  • Kaufman ES. Efficient genotyping for congenital long QT syndrome. JAMA. 2005 Dec 21;294(23):3027-8. PubMed PMID: 16414952.
  • Perez MV, Kumarasamy NA, Owens DK, Wang PJ, Hlatky MA. Cost-effectiveness of genetic testing in family members of patients with long-QT syndrome. Circ Cardiovasc Qual Outcomes. 2011 Jan 1;4(1):76-84. Epub 2010 Dec 7. PubMed PMID: 21139095.
  • Medica. Genetic testing for cardiac channelopathies: utilization management policy (number III-DIA.05). Available at: http://provider.medica.com/C10/PolicyUtilization/Document%20Library/IIIDIA05.pdf. Accessed 20 Feb 2012.
  • Hall AE, Burton H. Legal and ethical implications of inherited cardiac disease in clinical practice within the UK. J Med Ethics. 2010 Dec;36(12):762-6. PubMed PMID: 21112937.
  • Liebman J. Some legal, social, and ethical issues related to the genetic testing revolution, as exemplified in the long QT syndrome. J Electrocardiol. 2001;34 Suppl:183-8. PubMed PMID: 11781954.
  • Wren C. Screening children with a family history of sudden cardiac death. Heart. 2006 Jul;92(7):1001-6. Review. PubMed PMID: 16775115; PubMed Central PMCID: PMC1860723.
  • Schwartz PJ, Spazzolini C, Priori SG, Crotti L, Vicentini A, Landolina M, Gasparini M, Wilde AA, Knops RE, Denjoy I, Toivonen L, Mönnig G, Al-Fayyadh M, Jordaens L, Borggrefe M, Holmgren C, Brugada P, De Roy L, Hohnloser SH, Brink PA. Who are the long-QT syndrome patients who receive an implantable cardioverter-defibrillator and what happens to them?: data from the European Long-QT Syndrome Implantable Cardioverter-Defibrillator (LQTS ICD) Registry. Circulation. 2010 Sep 28;122(13):1272-82. Epub 2010 Sep 13. PubMed PMID: 20837891.

Leave a Comment