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/Title (SCN1A Genetic Test for Dravet Syndrome \(Severe Myoclonic Epilepsy of Infancy and its Clinical Subtypes\) for use in the Diagnosis, Prognosis, Treatment and Management of Dravet Syndrome � PLOS Currents Evidence on Genomic Tests)
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BT 15.000 718.042 Td /F2 21.0 Tf  [(SCN1A Genetic Test for Dravet Syndrome \(Severe Myoclonic )] TJ ET
BT 15.000 693.094 Td /F2 21.0 Tf  [(Epilepsy of Infancy and its Clinical Subtypes\) for use in the )] TJ ET
BT 15.000 668.146 Td /F2 21.0 Tf  [(Diagnosis, Prognosis, Treatment and Management of Dravet )] TJ ET
BT 15.000 643.198 Td /F2 21.0 Tf  [(Syndrome)] TJ ET
Q
0.271 0.267 0.267 rg
BT 15.000 625.192 Td /F3 9.8 Tf  [(April 25, 2013)] TJ ET
BT 76.483 625.192 Td /F3 9.8 Tf  [(�)] TJ ET
0.267 0.267 0.267 rg
BT 81.358 625.192 Td /F3 9.8 Tf  [(Diagnostic)] TJ ET
BT 26.250 613.351 Td /F1 9.8 Tf  [(Susan A.R. Stenhouse)] TJ ET
0.271 0.267 0.267 rg
BT 124.891 617.239 Td /F1 8.7 Tf  [(1)] TJ ET
BT 129.709 613.351 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 135.130 613.351 Td /F1 9.8 Tf  [(Rachael Ellis)] TJ ET
0.271 0.267 0.267 rg
BT 191.476 613.351 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 196.897 613.351 Td /F1 9.8 Tf  [(Sameer Zuberi)] TJ ET
0.271 0.267 0.267 rg
BT 261.373 617.239 Td /F1 8.7 Tf  [(2)] TJ ET
BT 26.250 602.179 Td /F4 9.0 Tf  [(1)] TJ ET
BT 31.254 602.179 Td /F1 9.0 Tf  [( UK Genetic Testing Network, )] TJ ET
BT 152.295 602.179 Td /F4 9.0 Tf  [(2)] TJ ET
BT 157.299 602.179 Td /F1 9.0 Tf  [( Royal Hospital for Sick Children)] TJ ET
BT 26.250 590.457 Td /F1 9.8 Tf  [(Stenhouse SA, Ellis R, Zuberi S. SCN1A Genetic Test for Dravet Syndrome \(Severe Myoclonic Epilepsy of Infancy and its )] TJ ET
BT 26.250 578.553 Td /F1 9.8 Tf  [(Clinical Subtypes\) for use in the Diagnosis, Prognosis, Treatment and Management of Dravet Syndrome. PLOS Currents )] TJ ET
BT 26.250 566.648 Td /F1 9.8 Tf  [(Evidence on Genomic Tests. 2013 Apr 25 . Edition 1. doi: 10.1371/currents.eogt.c553b83d745dd79bfb61eaf35e522b0b.)] TJ ET
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BT 26.250 537.545 Td /F4 12.0 Tf  [(Abstract)] TJ ET
BT 26.250 517.591 Td /F1 9.8 Tf  [(Classic Dravet syndrome is also termed severe myoclonic epilepsy of infancy \(SMEI\). There are subtle phenotypic variants of )] TJ ET
BT 26.250 505.686 Td /F1 9.8 Tf  [(Dravet which may have all the features of the syndrome except one, such as without myoclonic seizures, onset in the second )] TJ ET
BT 26.250 493.782 Td /F1 9.8 Tf  [(year or without generalized spike and wave on EEG. These have been termed borderline variants of SMEI. Rather than )] TJ ET
BT 26.250 481.877 Td /F1 9.8 Tf  [(ascribing multiple different names to marginally different phenotypes, the term Dravet syndrome is now preferred to describe the )] TJ ET
BT 26.250 469.972 Td /F1 9.8 Tf  [(group of severe infantile onset epilepsies \(OMIM #607208, #182389, #604403\) associated with mutations in SCN1A \(OMIM )] TJ ET
BT 26.250 458.067 Td /F1 9.8 Tf  [(*182389\).)] TJ ET
BT 26.250 438.663 Td /F1 9.8 Tf  [(SCN1A-related seizure disorders can be inherited in an autosomal dominant manner but most are due to de novo mutations. )] TJ ET
BT 26.250 426.758 Td /F1 9.8 Tf  [(SCN1A testing can be done through bi-directional DNA sequencing and multiplex ligation-dependent probe amplification )] TJ ET
BT 26.250 414.853 Td /F1 9.8 Tf  [(\(MLPA\) for:)] TJ ET
BT 26.250 402.948 Td /F1 9.8 Tf  [(1\) individuals with electroclinical phenotype of Dravet Syndrome or clinical sub-types � several seizure types in one individual )] TJ ET
BT 26.250 391.044 Td /F1 9.8 Tf  [(with onset in infancy, refractory to medication and with generalised spike and wave on EEG, or)] TJ ET
BT 26.250 379.139 Td /F1 9.8 Tf  [(2\) infants less than 1 year old with 2 or more prolonged hemiclonic febrile seizures in early infancy.)] TJ ET
BT 26.250 359.734 Td /F1 9.8 Tf  [(Disclaimer: This summary is based on a UK Genetic Testing Network \(UKGTN\) approved Gene Dossier application.)] TJ ET
BT 26.250 323.132 Td /F4 12.0 Tf  [(Funding Statement)] TJ ET
BT 26.250 303.177 Td /F1 9.8 Tf  [(The SCN1A testing service in the West of Scotland Molecular Genetics Department is funded for the population of Scotland by )] TJ ET
BT 26.250 291.273 Td /F1 9.8 Tf  [(National Services Division \(Scotland\) as part of the Scottish Genetics Laboratory Consortium.)] TJ ET
BT 26.250 262.170 Td /F4 12.0 Tf  [(Clinical Scenario)] TJ ET
BT 26.250 242.216 Td /F1 9.8 Tf  [(Test for epilepsy syndromes associated with mutations in the SCN1A gene including the severe infantile onset epilepsies- )] TJ ET
BT 26.250 230.311 Td /F1 9.8 Tf  [(typical Dravet syndrome \(severe myoclonic epilepsy in infancy\) and its borderline subtypes. Dravet syndrome typically presents )] TJ ET
BT 26.250 218.406 Td /F1 9.8 Tf  [(in the first year of life with prolonged febrile and non-febrile, generalised clonic or hemiclonic epileptic seizures in children with )] TJ ET
BT 26.250 206.502 Td /F1 9.8 Tf  [(no pre-existing developmental problems. Other seizure types including myoclonic, focal and atypical absence seizures appear )] TJ ET
BT 26.250 194.597 Td /F1 9.8 Tf  [(between the ages of one and four years. The epilepsy is usually refractory to standard anti-epileptic medication and from the )] TJ ET
BT 26.250 182.692 Td /F1 9.8 Tf  [(second year of life affected children develop an epileptic encephalopathy resulting in cognitive, behavioural and motor )] TJ ET
BT 26.250 170.787 Td /F1 9.8 Tf  [(impairment. Seizure types within Dravet syndrome such as status epilepticus may be life threatening and sudden unexpected )] TJ ET
BT 26.250 158.883 Td /F1 9.8 Tf  [(death in epilepsy can occur. Despite the phenotypic variability within the typical and borderline forms they are now all classified )] TJ ET
BT 26.250 146.978 Td /F1 9.8 Tf  [(together as Dravet syndrome.)] TJ ET
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39.522 132.063 39.078 132.247 38.631 132.247 c
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37.109 131.431 36.925 130.987 36.925 130.541 c
36.925 130.094 37.109 129.650 37.425 129.334 c
37.741 129.018 38.185 128.834 38.631 128.834 c
39.078 128.834 39.522 129.018 39.838 129.334 c
40.154 129.650 40.337 130.094 40.337 130.541 c f
BT 45.750 127.573 Td /F1 9.8 Tf  [(Referrals made by paediatric neurologists, neurologists, epileptologists, paediatricians, clinical geneticists.)] TJ ET
40.337 114.886 m 
40.337 115.333 40.154 115.777 39.838 116.093 c
39.522 116.408 39.078 116.592 38.631 116.592 c
38.185 116.592 37.741 116.408 37.425 116.093 c
37.109 115.777 36.925 115.333 36.925 114.886 c
36.925 114.439 37.109 113.995 37.425 113.679 c
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39.078 113.180 39.522 113.364 39.838 113.679 c
40.154 113.995 40.337 114.439 40.337 114.886 c f
BT 45.750 111.918 Td /F1 9.8 Tf  [(Sample processed for SCN1A mutation screening.)] TJ ET
40.337 99.231 m 
40.337 99.678 40.154 100.122 39.838 100.438 c
39.522 100.754 39.078 100.937 38.631 100.937 c
38.185 100.937 37.741 100.754 37.425 100.438 c
37.109 100.122 36.925 99.678 36.925 99.231 c
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37.741 97.709 38.185 97.525 38.631 97.525 c
39.078 97.525 39.522 97.709 39.838 98.025 c
40.154 98.341 40.337 98.785 40.337 99.231 c f
BT 45.750 96.264 Td /F1 9.8 Tf  [(Target population includes those with electroclinical phenotype of Dravet Syndrome or clinical sub-types � several seizure )] TJ ET
BT 45.750 84.359 Td /F1 9.8 Tf  [(types in one individual with onset in infancy, refractory to medication and with generalised spike and wave on EEG or )] TJ ET
BT 45.750 72.454 Td /F1 9.8 Tf  [(infants less than 1 year with 2 or more prolonged hemiclonic febrile seizures in early infancy.)] TJ ET
40.337 59.767 m 
40.337 60.214 40.154 60.658 39.838 60.974 c
39.522 61.289 39.078 61.473 38.631 61.473 c
38.185 61.473 37.741 61.289 37.425 60.974 c
37.109 60.658 36.925 60.214 36.925 59.767 c
36.925 59.320 37.109 58.876 37.425 58.560 c
37.741 58.245 38.185 58.061 38.631 58.061 c
39.078 58.061 39.522 58.245 39.838 58.560 c
40.154 58.876 40.337 59.320 40.337 59.767 c f
BT 45.750 56.799 Td /F1 9.8 Tf  [(The estimated likelihood of detecting an SCN1A mutation in a typical Dravet case is 80-90%.)] TJ ET
40.337 44.112 m 
40.337 44.559 40.154 45.003 39.838 45.319 c
39.522 45.635 39.078 45.818 38.631 45.818 c
38.185 45.818 37.741 45.635 37.425 45.319 c
37.109 45.003 36.925 44.559 36.925 44.112 c
36.925 43.666 37.109 43.222 37.425 42.906 c
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39.078 42.406 39.522 42.590 39.838 42.906 c
40.154 43.222 40.337 43.666 40.337 44.112 c f
BT 45.750 41.145 Td /F1 9.8 Tf  [(This test is for use in the diagnosis, prognosis, treatment and management of Dravet Syndrome.)] TJ ET
Q
q
15.000 634.458 577.500 103.542 re W n
0.267 0.267 0.267 rg
BT 15.000 718.042 Td /F2 21.0 Tf  [(SCN1A Genetic Test for Dravet Syndrome \(Severe Myoclonic )] TJ ET
BT 15.000 693.094 Td /F2 21.0 Tf  [(Epilepsy of Infancy and its Clinical Subtypes\) for use in the )] TJ ET
BT 15.000 668.146 Td /F2 21.0 Tf  [(Diagnosis, Prognosis, Treatment and Management of Dravet )] TJ ET
BT 15.000 643.198 Td /F2 21.0 Tf  [(Syndrome)] TJ ET
Q
0.271 0.267 0.267 rg
BT 15.000 625.192 Td /F3 9.8 Tf  [(April 25, 2013)] TJ ET
BT 76.483 625.192 Td /F3 9.8 Tf  [(�)] TJ ET
0.267 0.267 0.267 rg
BT 81.358 625.192 Td /F3 9.8 Tf  [(Diagnostic)] TJ ET
BT 26.250 613.351 Td /F1 9.8 Tf  [(Susan A.R. Stenhouse)] TJ ET
0.271 0.267 0.267 rg
BT 124.891 617.239 Td /F1 8.7 Tf  [(1)] TJ ET
BT 129.709 613.351 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 135.130 613.351 Td /F1 9.8 Tf  [(Rachael Ellis)] TJ ET
0.271 0.267 0.267 rg
BT 191.476 613.351 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 196.897 613.351 Td /F1 9.8 Tf  [(Sameer Zuberi)] TJ ET
0.271 0.267 0.267 rg
BT 261.373 617.239 Td /F1 8.7 Tf  [(2)] TJ ET
BT 26.250 602.179 Td /F4 9.0 Tf  [(1)] TJ ET
BT 31.254 602.179 Td /F1 9.0 Tf  [( UK Genetic Testing Network, )] TJ ET
BT 152.295 602.179 Td /F4 9.0 Tf  [(2)] TJ ET
BT 157.299 602.179 Td /F1 9.0 Tf  [( Royal Hospital for Sick Children)] TJ ET
BT 26.250 590.457 Td /F1 9.8 Tf  [(Stenhouse SA, Ellis R, Zuberi S. SCN1A Genetic Test for Dravet Syndrome \(Severe Myoclonic Epilepsy of Infancy and its )] TJ ET
BT 26.250 578.553 Td /F1 9.8 Tf  [(Clinical Subtypes\) for use in the Diagnosis, Prognosis, Treatment and Management of Dravet Syndrome. PLOS Currents )] TJ ET
BT 26.250 566.648 Td /F1 9.8 Tf  [(Evidence on Genomic Tests. 2013 Apr 25 . Edition 1. doi: 10.1371/currents.eogt.c553b83d745dd79bfb61eaf35e522b0b.)] TJ ET
q
15.000 35.014 577.500 529.253 re W n
0.271 0.267 0.267 rg
BT 26.250 537.545 Td /F4 12.0 Tf  [(Abstract)] TJ ET
BT 26.250 517.591 Td /F1 9.8 Tf  [(Classic Dravet syndrome is also termed severe myoclonic epilepsy of infancy \(SMEI\). There are subtle phenotypic variants of )] TJ ET
BT 26.250 505.686 Td /F1 9.8 Tf  [(Dravet which may have all the features of the syndrome except one, such as without myoclonic seizures, onset in the second )] TJ ET
BT 26.250 493.782 Td /F1 9.8 Tf  [(year or without generalized spike and wave on EEG. These have been termed borderline variants of SMEI. Rather than )] TJ ET
BT 26.250 481.877 Td /F1 9.8 Tf  [(ascribing multiple different names to marginally different phenotypes, the term Dravet syndrome is now preferred to describe the )] TJ ET
BT 26.250 469.972 Td /F1 9.8 Tf  [(group of severe infantile onset epilepsies \(OMIM #607208, #182389, #604403\) associated with mutations in SCN1A \(OMIM )] TJ ET
BT 26.250 458.067 Td /F1 9.8 Tf  [(*182389\).)] TJ ET
BT 26.250 438.663 Td /F1 9.8 Tf  [(SCN1A-related seizure disorders can be inherited in an autosomal dominant manner but most are due to de novo mutations. )] TJ ET
BT 26.250 426.758 Td /F1 9.8 Tf  [(SCN1A testing can be done through bi-directional DNA sequencing and multiplex ligation-dependent probe amplification )] TJ ET
BT 26.250 414.853 Td /F1 9.8 Tf  [(\(MLPA\) for:)] TJ ET
BT 26.250 402.948 Td /F1 9.8 Tf  [(1\) individuals with electroclinical phenotype of Dravet Syndrome or clinical sub-types � several seizure types in one individual )] TJ ET
BT 26.250 391.044 Td /F1 9.8 Tf  [(with onset in infancy, refractory to medication and with generalised spike and wave on EEG, or)] TJ ET
BT 26.250 379.139 Td /F1 9.8 Tf  [(2\) infants less than 1 year old with 2 or more prolonged hemiclonic febrile seizures in early infancy.)] TJ ET
BT 26.250 359.734 Td /F1 9.8 Tf  [(Disclaimer: This summary is based on a UK Genetic Testing Network \(UKGTN\) approved Gene Dossier application.)] TJ ET
BT 26.250 323.132 Td /F4 12.0 Tf  [(Funding Statement)] TJ ET
BT 26.250 303.177 Td /F1 9.8 Tf  [(The SCN1A testing service in the West of Scotland Molecular Genetics Department is funded for the population of Scotland by )] TJ ET
BT 26.250 291.273 Td /F1 9.8 Tf  [(National Services Division \(Scotland\) as part of the Scottish Genetics Laboratory Consortium.)] TJ ET
BT 26.250 262.170 Td /F4 12.0 Tf  [(Clinical Scenario)] TJ ET
BT 26.250 242.216 Td /F1 9.8 Tf  [(Test for epilepsy syndromes associated with mutations in the SCN1A gene including the severe infantile onset epilepsies- )] TJ ET
BT 26.250 230.311 Td /F1 9.8 Tf  [(typical Dravet syndrome \(severe myoclonic epilepsy in infancy\) and its borderline subtypes. Dravet syndrome typically presents )] TJ ET
BT 26.250 218.406 Td /F1 9.8 Tf  [(in the first year of life with prolonged febrile and non-febrile, generalised clonic or hemiclonic epileptic seizures in children with )] TJ ET
BT 26.250 206.502 Td /F1 9.8 Tf  [(no pre-existing developmental problems. Other seizure types including myoclonic, focal and atypical absence seizures appear )] TJ ET
BT 26.250 194.597 Td /F1 9.8 Tf  [(between the ages of one and four years. The epilepsy is usually refractory to standard anti-epileptic medication and from the )] TJ ET
BT 26.250 182.692 Td /F1 9.8 Tf  [(second year of life affected children develop an epileptic encephalopathy resulting in cognitive, behavioural and motor )] TJ ET
BT 26.250 170.787 Td /F1 9.8 Tf  [(impairment. Seizure types within Dravet syndrome such as status epilepticus may be life threatening and sudden unexpected )] TJ ET
BT 26.250 158.883 Td /F1 9.8 Tf  [(death in epilepsy can occur. Despite the phenotypic variability within the typical and borderline forms they are now all classified )] TJ ET
BT 26.250 146.978 Td /F1 9.8 Tf  [(together as Dravet syndrome.)] TJ ET
0.271 0.267 0.267 RG
40.337 130.541 m 
40.337 130.987 40.154 131.431 39.838 131.747 c
39.522 132.063 39.078 132.247 38.631 132.247 c
38.185 132.247 37.741 132.063 37.425 131.747 c
37.109 131.431 36.925 130.987 36.925 130.541 c
36.925 130.094 37.109 129.650 37.425 129.334 c
37.741 129.018 38.185 128.834 38.631 128.834 c
39.078 128.834 39.522 129.018 39.838 129.334 c
40.154 129.650 40.337 130.094 40.337 130.541 c f
BT 45.750 127.573 Td /F1 9.8 Tf  [(Referrals made by paediatric neurologists, neurologists, epileptologists, paediatricians, clinical geneticists.)] TJ ET
40.337 114.886 m 
40.337 115.333 40.154 115.777 39.838 116.093 c
39.522 116.408 39.078 116.592 38.631 116.592 c
38.185 116.592 37.741 116.408 37.425 116.093 c
37.109 115.777 36.925 115.333 36.925 114.886 c
36.925 114.439 37.109 113.995 37.425 113.679 c
37.741 113.364 38.185 113.180 38.631 113.180 c
39.078 113.180 39.522 113.364 39.838 113.679 c
40.154 113.995 40.337 114.439 40.337 114.886 c f
BT 45.750 111.918 Td /F1 9.8 Tf  [(Sample processed for SCN1A mutation screening.)] TJ ET
40.337 99.231 m 
40.337 99.678 40.154 100.122 39.838 100.438 c
39.522 100.754 39.078 100.937 38.631 100.937 c
38.185 100.937 37.741 100.754 37.425 100.438 c
37.109 100.122 36.925 99.678 36.925 99.231 c
36.925 98.785 37.109 98.341 37.425 98.025 c
37.741 97.709 38.185 97.525 38.631 97.525 c
39.078 97.525 39.522 97.709 39.838 98.025 c
40.154 98.341 40.337 98.785 40.337 99.231 c f
BT 45.750 96.264 Td /F1 9.8 Tf  [(Target population includes those with electroclinical phenotype of Dravet Syndrome or clinical sub-types � several seizure )] TJ ET
BT 45.750 84.359 Td /F1 9.8 Tf  [(types in one individual with onset in infancy, refractory to medication and with generalised spike and wave on EEG or )] TJ ET
BT 45.750 72.454 Td /F1 9.8 Tf  [(infants less than 1 year with 2 or more prolonged hemiclonic febrile seizures in early infancy.)] TJ ET
40.337 59.767 m 
40.337 60.214 40.154 60.658 39.838 60.974 c
39.522 61.289 39.078 61.473 38.631 61.473 c
38.185 61.473 37.741 61.289 37.425 60.974 c
37.109 60.658 36.925 60.214 36.925 59.767 c
36.925 59.320 37.109 58.876 37.425 58.560 c
37.741 58.245 38.185 58.061 38.631 58.061 c
39.078 58.061 39.522 58.245 39.838 58.560 c
40.154 58.876 40.337 59.320 40.337 59.767 c f
BT 45.750 56.799 Td /F1 9.8 Tf  [(The estimated likelihood of detecting an SCN1A mutation in a typical Dravet case is 80-90%.)] TJ ET
40.337 44.112 m 
40.337 44.559 40.154 45.003 39.838 45.319 c
39.522 45.635 39.078 45.818 38.631 45.818 c
38.185 45.818 37.741 45.635 37.425 45.319 c
37.109 45.003 36.925 44.559 36.925 44.112 c
36.925 43.666 37.109 43.222 37.425 42.906 c
37.741 42.590 38.185 42.406 38.631 42.406 c
39.078 42.406 39.522 42.590 39.838 42.906 c
40.154 43.222 40.337 43.666 40.337 44.112 c f
BT 45.750 41.145 Td /F1 9.8 Tf  [(This test is for use in the diagnosis, prognosis, treatment and management of Dravet Syndrome.)] TJ ET
Q
q
15.000 634.458 577.500 103.542 re W n
0.267 0.267 0.267 rg
BT 15.000 718.042 Td /F2 21.0 Tf  [(SCN1A Genetic Test for Dravet Syndrome \(Severe Myoclonic )] TJ ET
BT 15.000 693.094 Td /F2 21.0 Tf  [(Epilepsy of Infancy and its Clinical Subtypes\) for use in the )] TJ ET
BT 15.000 668.146 Td /F2 21.0 Tf  [(Diagnosis, Prognosis, Treatment and Management of Dravet )] TJ ET
BT 15.000 643.198 Td /F2 21.0 Tf  [(Syndrome)] TJ ET
Q
0.271 0.267 0.267 rg
BT 15.000 625.192 Td /F3 9.8 Tf  [(April 25, 2013)] TJ ET
BT 76.483 625.192 Td /F3 9.8 Tf  [(�)] TJ ET
0.267 0.267 0.267 rg
BT 81.358 625.192 Td /F3 9.8 Tf  [(Diagnostic)] TJ ET
BT 26.250 613.351 Td /F1 9.8 Tf  [(Susan A.R. Stenhouse)] TJ ET
0.271 0.267 0.267 rg
BT 124.891 617.239 Td /F1 8.7 Tf  [(1)] TJ ET
BT 129.709 613.351 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 135.130 613.351 Td /F1 9.8 Tf  [(Rachael Ellis)] TJ ET
0.271 0.267 0.267 rg
BT 191.476 613.351 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 196.897 613.351 Td /F1 9.8 Tf  [(Sameer Zuberi)] TJ ET
0.271 0.267 0.267 rg
BT 261.373 617.239 Td /F1 8.7 Tf  [(2)] TJ ET
BT 26.250 602.179 Td /F4 9.0 Tf  [(1)] TJ ET
BT 31.254 602.179 Td /F1 9.0 Tf  [( UK Genetic Testing Network, )] TJ ET
BT 152.295 602.179 Td /F4 9.0 Tf  [(2)] TJ ET
BT 157.299 602.179 Td /F1 9.0 Tf  [( Royal Hospital for Sick Children)] TJ ET
BT 26.250 590.457 Td /F1 9.8 Tf  [(Stenhouse SA, Ellis R, Zuberi S. SCN1A Genetic Test for Dravet Syndrome \(Severe Myoclonic Epilepsy of Infancy and its )] TJ ET
BT 26.250 578.553 Td /F1 9.8 Tf  [(Clinical Subtypes\) for use in the Diagnosis, Prognosis, Treatment and Management of Dravet Syndrome. PLOS Currents )] TJ ET
BT 26.250 566.648 Td /F1 9.8 Tf  [(Evidence on Genomic Tests. 2013 Apr 25 . Edition 1. doi: 10.1371/currents.eogt.c553b83d745dd79bfb61eaf35e522b0b.)] TJ ET
q
15.000 35.014 577.500 529.253 re W n
0.271 0.267 0.267 rg
BT 26.250 537.545 Td /F4 12.0 Tf  [(Abstract)] TJ ET
BT 26.250 517.591 Td /F1 9.8 Tf  [(Classic Dravet syndrome is also termed severe myoclonic epilepsy of infancy \(SMEI\). There are subtle phenotypic variants of )] TJ ET
BT 26.250 505.686 Td /F1 9.8 Tf  [(Dravet which may have all the features of the syndrome except one, such as without myoclonic seizures, onset in the second )] TJ ET
BT 26.250 493.782 Td /F1 9.8 Tf  [(year or without generalized spike and wave on EEG. These have been termed borderline variants of SMEI. Rather than )] TJ ET
BT 26.250 481.877 Td /F1 9.8 Tf  [(ascribing multiple different names to marginally different phenotypes, the term Dravet syndrome is now preferred to describe the )] TJ ET
BT 26.250 469.972 Td /F1 9.8 Tf  [(group of severe infantile onset epilepsies \(OMIM #607208, #182389, #604403\) associated with mutations in SCN1A \(OMIM )] TJ ET
BT 26.250 458.067 Td /F1 9.8 Tf  [(*182389\).)] TJ ET
BT 26.250 438.663 Td /F1 9.8 Tf  [(SCN1A-related seizure disorders can be inherited in an autosomal dominant manner but most are due to de novo mutations. )] TJ ET
BT 26.250 426.758 Td /F1 9.8 Tf  [(SCN1A testing can be done through bi-directional DNA sequencing and multiplex ligation-dependent probe amplification )] TJ ET
BT 26.250 414.853 Td /F1 9.8 Tf  [(\(MLPA\) for:)] TJ ET
BT 26.250 402.948 Td /F1 9.8 Tf  [(1\) individuals with electroclinical phenotype of Dravet Syndrome or clinical sub-types � several seizure types in one individual )] TJ ET
BT 26.250 391.044 Td /F1 9.8 Tf  [(with onset in infancy, refractory to medication and with generalised spike and wave on EEG, or)] TJ ET
BT 26.250 379.139 Td /F1 9.8 Tf  [(2\) infants less than 1 year old with 2 or more prolonged hemiclonic febrile seizures in early infancy.)] TJ ET
BT 26.250 359.734 Td /F1 9.8 Tf  [(Disclaimer: This summary is based on a UK Genetic Testing Network \(UKGTN\) approved Gene Dossier application.)] TJ ET
BT 26.250 323.132 Td /F4 12.0 Tf  [(Funding Statement)] TJ ET
BT 26.250 303.177 Td /F1 9.8 Tf  [(The SCN1A testing service in the West of Scotland Molecular Genetics Department is funded for the population of Scotland by )] TJ ET
BT 26.250 291.273 Td /F1 9.8 Tf  [(National Services Division \(Scotland\) as part of the Scottish Genetics Laboratory Consortium.)] TJ ET
BT 26.250 262.170 Td /F4 12.0 Tf  [(Clinical Scenario)] TJ ET
BT 26.250 242.216 Td /F1 9.8 Tf  [(Test for epilepsy syndromes associated with mutations in the SCN1A gene including the severe infantile onset epilepsies- )] TJ ET
BT 26.250 230.311 Td /F1 9.8 Tf  [(typical Dravet syndrome \(severe myoclonic epilepsy in infancy\) and its borderline subtypes. Dravet syndrome typically presents )] TJ ET
BT 26.250 218.406 Td /F1 9.8 Tf  [(in the first year of life with prolonged febrile and non-febrile, generalised clonic or hemiclonic epileptic seizures in children with )] TJ ET
BT 26.250 206.502 Td /F1 9.8 Tf  [(no pre-existing developmental problems. Other seizure types including myoclonic, focal and atypical absence seizures appear )] TJ ET
BT 26.250 194.597 Td /F1 9.8 Tf  [(between the ages of one and four years. The epilepsy is usually refractory to standard anti-epileptic medication and from the )] TJ ET
BT 26.250 182.692 Td /F1 9.8 Tf  [(second year of life affected children develop an epileptic encephalopathy resulting in cognitive, behavioural and motor )] TJ ET
BT 26.250 170.787 Td /F1 9.8 Tf  [(impairment. Seizure types within Dravet syndrome such as status epilepticus may be life threatening and sudden unexpected )] TJ ET
BT 26.250 158.883 Td /F1 9.8 Tf  [(death in epilepsy can occur. Despite the phenotypic variability within the typical and borderline forms they are now all classified )] TJ ET
BT 26.250 146.978 Td /F1 9.8 Tf  [(together as Dravet syndrome.)] TJ ET
0.271 0.267 0.267 RG
40.337 130.541 m 
40.337 130.987 40.154 131.431 39.838 131.747 c
39.522 132.063 39.078 132.247 38.631 132.247 c
38.185 132.247 37.741 132.063 37.425 131.747 c
37.109 131.431 36.925 130.987 36.925 130.541 c
36.925 130.094 37.109 129.650 37.425 129.334 c
37.741 129.018 38.185 128.834 38.631 128.834 c
39.078 128.834 39.522 129.018 39.838 129.334 c
40.154 129.650 40.337 130.094 40.337 130.541 c f
BT 45.750 127.573 Td /F1 9.8 Tf  [(Referrals made by paediatric neurologists, neurologists, epileptologists, paediatricians, clinical geneticists.)] TJ ET
40.337 114.886 m 
40.337 115.333 40.154 115.777 39.838 116.093 c
39.522 116.408 39.078 116.592 38.631 116.592 c
38.185 116.592 37.741 116.408 37.425 116.093 c
37.109 115.777 36.925 115.333 36.925 114.886 c
36.925 114.439 37.109 113.995 37.425 113.679 c
37.741 113.364 38.185 113.180 38.631 113.180 c
39.078 113.180 39.522 113.364 39.838 113.679 c
40.154 113.995 40.337 114.439 40.337 114.886 c f
BT 45.750 111.918 Td /F1 9.8 Tf  [(Sample processed for SCN1A mutation screening.)] TJ ET
40.337 99.231 m 
40.337 99.678 40.154 100.122 39.838 100.438 c
39.522 100.754 39.078 100.937 38.631 100.937 c
38.185 100.937 37.741 100.754 37.425 100.438 c
37.109 100.122 36.925 99.678 36.925 99.231 c
36.925 98.785 37.109 98.341 37.425 98.025 c
37.741 97.709 38.185 97.525 38.631 97.525 c
39.078 97.525 39.522 97.709 39.838 98.025 c
40.154 98.341 40.337 98.785 40.337 99.231 c f
BT 45.750 96.264 Td /F1 9.8 Tf  [(Target population includes those with electroclinical phenotype of Dravet Syndrome or clinical sub-types � several seizure )] TJ ET
BT 45.750 84.359 Td /F1 9.8 Tf  [(types in one individual with onset in infancy, refractory to medication and with generalised spike and wave on EEG or )] TJ ET
BT 45.750 72.454 Td /F1 9.8 Tf  [(infants less than 1 year with 2 or more prolonged hemiclonic febrile seizures in early infancy.)] TJ ET
40.337 59.767 m 
40.337 60.214 40.154 60.658 39.838 60.974 c
39.522 61.289 39.078 61.473 38.631 61.473 c
38.185 61.473 37.741 61.289 37.425 60.974 c
37.109 60.658 36.925 60.214 36.925 59.767 c
36.925 59.320 37.109 58.876 37.425 58.560 c
37.741 58.245 38.185 58.061 38.631 58.061 c
39.078 58.061 39.522 58.245 39.838 58.560 c
40.154 58.876 40.337 59.320 40.337 59.767 c f
BT 45.750 56.799 Td /F1 9.8 Tf  [(The estimated likelihood of detecting an SCN1A mutation in a typical Dravet case is 80-90%.)] TJ ET
40.337 44.112 m 
40.337 44.559 40.154 45.003 39.838 45.319 c
39.522 45.635 39.078 45.818 38.631 45.818 c
38.185 45.818 37.741 45.635 37.425 45.319 c
37.109 45.003 36.925 44.559 36.925 44.112 c
36.925 43.666 37.109 43.222 37.425 42.906 c
37.741 42.590 38.185 42.406 38.631 42.406 c
39.078 42.406 39.522 42.590 39.838 42.906 c
40.154 43.222 40.337 43.666 40.337 44.112 c f
BT 45.750 41.145 Td /F1 9.8 Tf  [(This test is for use in the diagnosis, prognosis, treatment and management of Dravet Syndrome.)] TJ ET
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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 45.750 767.476 Td /F1 9.8 Tf  [(OMIM number for disease #607208, #182389, #604403)] TJ ET
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BT 45.750 751.821 Td /F1 9.8 Tf  [(Gene � name and description � SCN1A, Sodium channel, neuronal type 1, alpha subunit)] TJ ET
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BT 45.750 720.512 Td /F1 9.8 Tf  [(Technical Method \(s\) Bi-directional DNA sequencing)] TJ ET
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BT 45.750 704.857 Td /F1 9.8 Tf  [(Multiplex Ligation-dependent Probe Amplification \(MLPA\))] TJ ET
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BT 226.702 442.041 Td /F1 9.8 Tf  [( .)] TJ ET
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BT 26.250 379.422 Td /F1 9.8 Tf  [(A confirmed diagnosis has implications for treatment stragegies and genetic counseling. It can save many additional costly and )] TJ ET
BT 26.250 367.518 Td /F1 9.8 Tf  [(invasive investigations. When a diagnosis confirms or supports a clinical suspicion, medication changes may result )] TJ ET
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BT 26.250 69.642 Td /F1 9.8 Tf  [(Diagnostic testing methodologies:\(DNA sequencing\) Mutation scanning in single direction confirmed in opposite direction and )] TJ ET
BT 26.250 57.738 Td /F1 9.8 Tf  [(again in an exon specific separate assay. All primers are SNP and BLAST alignment checked. All mutations identified in a )] TJ ET
BT 26.250 45.833 Td /F1 9.8 Tf  [(previous preliminary project were confirmed using this methodology. This methodology is well established in the laboratory for )] TJ ET
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BT 45.750 767.476 Td /F1 9.8 Tf  [(OMIM number for disease #607208, #182389, #604403)] TJ ET
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BT 45.750 751.821 Td /F1 9.8 Tf  [(Gene � name and description � SCN1A, Sodium channel, neuronal type 1, alpha subunit)] TJ ET
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40.154 738.244 40.337 738.688 40.337 739.134 c f
BT 45.750 736.167 Td /F1 9.8 Tf  [(OMIM number for Gene *182389)] TJ ET
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39.078 721.773 39.522 721.957 39.838 722.273 c
40.154 722.589 40.337 723.033 40.337 723.480 c f
BT 45.750 720.512 Td /F1 9.8 Tf  [(Technical Method \(s\) Bi-directional DNA sequencing)] TJ ET
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40.337 708.271 40.154 708.715 39.838 709.031 c
39.522 709.347 39.078 709.531 38.631 709.531 c
38.185 709.531 37.741 709.347 37.425 709.031 c
37.109 708.715 36.925 708.271 36.925 707.825 c
36.925 707.378 37.109 706.934 37.425 706.618 c
37.741 706.302 38.185 706.119 38.631 706.119 c
39.078 706.119 39.522 706.302 39.838 706.618 c
40.154 706.934 40.337 707.378 40.337 707.825 c f
BT 45.750 704.857 Td /F1 9.8 Tf  [(Multiplex Ligation-dependent Probe Amplification \(MLPA\))] TJ ET
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BT 26.250 613.241 Td /F1 9.8 Tf  [(again in an exon specific separate assay. All primers are SNP and BLAST alignment checked. All mutations identified in a )] TJ ET
BT 26.250 601.336 Td /F1 9.8 Tf  [(previous preliminary project were confirmed using this methodology. This methodology is well established in the laboratory for )] TJ ET
BT 26.250 589.431 Td /F1 9.8 Tf  [(many disorders.)] TJ ET
BT 26.250 570.027 Td /F1 9.8 Tf  [(\(MLPA\) Use of an MLPA kit designed specifically to pick up deletions and duplications in the SCN1Agene. Exon 21 deletion )] TJ ET
BT 26.250 558.122 Td /F1 9.8 Tf  [(control identified amongst 10 normal control samples, assay repeated to validate results. This methodology is well established )] TJ ET
BT 26.250 546.217 Td /F1 9.8 Tf  [(in the laboratory for other disorders.)] TJ ET
BT 26.250 509.615 Td /F4 12.0 Tf  [(Public Health Importance)] TJ ET
BT 26.250 489.660 Td /F1 9.8 Tf  [(The estimated incidence of the disease in the UK population is difficult to ascertain as historically this group of epilepsy )] TJ ET
BT 26.250 477.756 Td /F1 9.8 Tf  [(syndromes have been excluded from epidemiological studies as they have been difficult to diagnose in electro-clinical terms )] TJ ET
0.267 0.267 0.267 rg
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0.271 0.267 0.267 rg
BT 567.543 477.756 Td /F1 9.8 Tf  [( . )] TJ ET
BT 26.250 465.851 Td /F1 9.8 Tf  [(A recent study based on a UK birth cohort suggested an incidence of at least 1 in 40,000 live births for SCN1A positive Dravet )] TJ ET
BT 26.250 453.946 Td /F1 9.8 Tf  [(syndrome and 1 in 29.000 for Dravet syndrome as a whole )] TJ ET
0.267 0.267 0.267 rg
BT 282.031 455.453 Td /F4 8.7 Tf  [(2)] TJ ET
0.271 0.267 0.267 rg
BT 286.850 453.946 Td /F1 9.8 Tf  [( . Dravet syndrome has been misdiagnosed as whooping cough )] TJ ET
BT 26.250 442.041 Td /F1 9.8 Tf  [(vaccine damage or pertussis encephalopathy)] TJ ET
0.267 0.267 0.267 rg
BT 221.884 443.549 Td /F4 8.7 Tf  [(3)] TJ ET
0.271 0.267 0.267 rg
BT 226.702 442.041 Td /F1 9.8 Tf  [( .)] TJ ET
BT 26.250 422.637 Td /F1 9.8 Tf  [(Where the mutation is inherited the inheritance pattern is autosomal dominant but most cases are found to be de novo. Familial )] TJ ET
BT 26.250 410.732 Td /F1 9.8 Tf  [(cases most commonly arise in Genetic Epilepsy with Febrile Seizures plus \(GEFS+\). The majority of cases are sporadic and the )] TJ ET
BT 26.250 398.827 Td /F1 9.8 Tf  [(great value of this test is providing an early diagnosis and allowing appropriate treatment. Penetrance is difficult to estimate.)] TJ ET
BT 26.250 379.422 Td /F1 9.8 Tf  [(A confirmed diagnosis has implications for treatment stragegies and genetic counseling. It can save many additional costly and )] TJ ET
BT 26.250 367.518 Td /F1 9.8 Tf  [(invasive investigations. When a diagnosis confirms or supports a clinical suspicion, medication changes may result )] TJ ET
0.267 0.267 0.267 rg
BT 523.139 369.025 Td /F4 8.7 Tf  [(4)] TJ ET
0.271 0.267 0.267 rg
BT 527.958 367.518 Td /F1 9.8 Tf  [(. Anti-)] TJ ET
BT 26.250 355.613 Td /F1 9.8 Tf  [(epileptic medications such as carbamazepine, lamtrigine and pheytoin can worsen seizures in Dravets syndrome whereas there )] TJ ET
BT 26.250 343.708 Td /F1 9.8 Tf  [(is evidence from placebo controlled trials that a medication called stirpentol in combination with valproate and clobazam may )] TJ ET
BT 26.250 331.803 Td /F1 9.8 Tf  [(reduce seizures. Infants with Dravet syndrome suffer from developmental regression and there is good evidence that some of )] TJ ET
BT 26.250 319.899 Td /F1 9.8 Tf  [(this is due to uncontrolled seizures and abnormal EEG activity \(an epileptic encephalopathy\). There is clinical justification and )] TJ ET
BT 26.250 307.994 Td /F1 9.8 Tf  [(evidence from recent research on adults with the syndrome to hope that controlling seizures will reduce the cognitive )] TJ ET
BT 26.250 296.089 Td /F1 9.8 Tf  [(impairment associated with the syndrome )] TJ ET
0.267 0.267 0.267 rg
BT 208.312 297.596 Td /F4 8.7 Tf  [(5)] TJ ET
0.271 0.267 0.267 rg
BT 213.130 296.089 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 276.684 Td /F1 9.8 Tf  [(The clinical features of Dravet Syndrome develop over several years so without the support of molecular genetic testing the )] TJ ET
BT 26.250 264.780 Td /F1 9.8 Tf  [(diagnosis may not be made until 2-4 years of age. By this time the child may have suffered years of uncontrolled seizures and )] TJ ET
BT 26.250 252.875 Td /F1 9.8 Tf  [(already have significant cognitive impairment )] TJ ET
0.267 0.267 0.267 rg
BT 222.946 254.382 Td /F4 8.7 Tf  [(2)] TJ ET
0.271 0.267 0.267 rg
BT 227.765 252.875 Td /F1 9.8 Tf  [( .)] TJ ET
BT 26.250 216.272 Td /F4 12.0 Tf  [(Published Reviews, Recommendations and Guidelines)] TJ ET
BT 26.250 196.318 Td /F5 9.8 Tf  [(Systematic evidence reviews:)] TJ ET
BT 163.900 196.318 Td /F1 9.8 Tf  [( None identified)] TJ ET
BT 26.250 176.913 Td /F5 9.8 Tf  [(Recommendations by independent group:)] TJ ET
BT 221.815 176.913 Td /F1 9.8 Tf  [(UKGTN � Gene Dossier)] TJ ET
BT 26.250 157.509 Td /F5 9.8 Tf  [(Guidelines by professional groups:)] TJ ET
BT 189.875 157.509 Td /F1 9.8 Tf  [(None identified)] TJ ET
BT 26.250 120.906 Td /F4 12.0 Tf  [(Evidence overview)] TJ ET
BT 26.250 100.952 Td /F5 9.8 Tf  [(Analytic Validity)] TJ ET
BT 101.569 100.952 Td /F4 9.8 Tf  [(: )] TJ ET
BT 107.526 100.952 Td /F1 9.8 Tf  [(Test accuracy and reliability in measuring analytes or other entities measured \(analytic sensitivity and )] TJ ET
BT 26.250 89.047 Td /F1 9.8 Tf  [(specificity\).)] TJ ET
BT 26.250 69.642 Td /F1 9.8 Tf  [(Diagnostic testing methodologies:\(DNA sequencing\) Mutation scanning in single direction confirmed in opposite direction and )] TJ ET
BT 26.250 57.738 Td /F1 9.8 Tf  [(again in an exon specific separate assay. All primers are SNP and BLAST alignment checked. All mutations identified in a )] TJ ET
BT 26.250 45.833 Td /F1 9.8 Tf  [(previous preliminary project were confirmed using this methodology. This methodology is well established in the laboratory for )] TJ ET
Q
q
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40.337 770.444 m 
40.337 770.890 40.154 771.334 39.838 771.650 c
39.522 771.966 39.078 772.150 38.631 772.150 c
38.185 772.150 37.741 771.966 37.425 771.650 c
37.109 771.334 36.925 770.890 36.925 770.444 c
36.925 769.997 37.109 769.553 37.425 769.237 c
37.741 768.921 38.185 768.738 38.631 768.738 c
39.078 768.738 39.522 768.921 39.838 769.237 c
40.154 769.553 40.337 769.997 40.337 770.444 c f
BT 45.750 767.476 Td /F1 9.8 Tf  [(OMIM number for disease #607208, #182389, #604403)] TJ ET
40.337 754.789 m 
40.337 755.236 40.154 755.680 39.838 755.996 c
39.522 756.311 39.078 756.495 38.631 756.495 c
38.185 756.495 37.741 756.311 37.425 755.996 c
37.109 755.680 36.925 755.236 36.925 754.789 c
36.925 754.342 37.109 753.898 37.425 753.582 c
37.741 753.267 38.185 753.083 38.631 753.083 c
39.078 753.083 39.522 753.267 39.838 753.582 c
40.154 753.898 40.337 754.342 40.337 754.789 c f
BT 45.750 751.821 Td /F1 9.8 Tf  [(Gene � name and description � SCN1A, Sodium channel, neuronal type 1, alpha subunit)] TJ ET
40.337 739.134 m 
40.337 739.581 40.154 740.025 39.838 740.341 c
39.522 740.657 39.078 740.840 38.631 740.840 c
38.185 740.840 37.741 740.657 37.425 740.341 c
37.109 740.025 36.925 739.581 36.925 739.134 c
36.925 738.688 37.109 738.244 37.425 737.928 c
37.741 737.612 38.185 737.428 38.631 737.428 c
39.078 737.428 39.522 737.612 39.838 737.928 c
40.154 738.244 40.337 738.688 40.337 739.134 c f
BT 45.750 736.167 Td /F1 9.8 Tf  [(OMIM number for Gene *182389)] TJ ET
40.337 723.480 m 
40.337 723.926 40.154 724.370 39.838 724.686 c
39.522 725.002 39.078 725.186 38.631 725.186 c
38.185 725.186 37.741 725.002 37.425 724.686 c
37.109 724.370 36.925 723.926 36.925 723.480 c
36.925 723.033 37.109 722.589 37.425 722.273 c
37.741 721.957 38.185 721.773 38.631 721.773 c
39.078 721.773 39.522 721.957 39.838 722.273 c
40.154 722.589 40.337 723.033 40.337 723.480 c f
BT 45.750 720.512 Td /F1 9.8 Tf  [(Technical Method \(s\) Bi-directional DNA sequencing)] TJ ET
40.337 707.825 m 
40.337 708.271 40.154 708.715 39.838 709.031 c
39.522 709.347 39.078 709.531 38.631 709.531 c
38.185 709.531 37.741 709.347 37.425 709.031 c
37.109 708.715 36.925 708.271 36.925 707.825 c
36.925 707.378 37.109 706.934 37.425 706.618 c
37.741 706.302 38.185 706.119 38.631 706.119 c
39.078 706.119 39.522 706.302 39.838 706.618 c
40.154 706.934 40.337 707.378 40.337 707.825 c f
BT 45.750 704.857 Td /F1 9.8 Tf  [(Multiplex Ligation-dependent Probe Amplification \(MLPA\))] TJ ET
BT 26.250 664.505 Td /F4 12.0 Tf  [(Test Description)] TJ ET
BT 26.250 644.550 Td /F1 9.8 Tf  [(Peripheral blood sample required.)] TJ ET
BT 26.250 625.146 Td /F1 9.8 Tf  [(Diagnostic testing methodologies:\(DNA sequencing\) Mutation scanning in single direction confirmed in opposite direction and )] TJ ET
BT 26.250 613.241 Td /F1 9.8 Tf  [(again in an exon specific separate assay. All primers are SNP and BLAST alignment checked. All mutations identified in a )] TJ ET
BT 26.250 601.336 Td /F1 9.8 Tf  [(previous preliminary project were confirmed using this methodology. This methodology is well established in the laboratory for )] TJ ET
BT 26.250 589.431 Td /F1 9.8 Tf  [(many disorders.)] TJ ET
BT 26.250 570.027 Td /F1 9.8 Tf  [(\(MLPA\) Use of an MLPA kit designed specifically to pick up deletions and duplications in the SCN1Agene. Exon 21 deletion )] TJ ET
BT 26.250 558.122 Td /F1 9.8 Tf  [(control identified amongst 10 normal control samples, assay repeated to validate results. This methodology is well established )] TJ ET
BT 26.250 546.217 Td /F1 9.8 Tf  [(in the laboratory for other disorders.)] TJ ET
BT 26.250 509.615 Td /F4 12.0 Tf  [(Public Health Importance)] TJ ET
BT 26.250 489.660 Td /F1 9.8 Tf  [(The estimated incidence of the disease in the UK population is difficult to ascertain as historically this group of epilepsy )] TJ ET
BT 26.250 477.756 Td /F1 9.8 Tf  [(syndromes have been excluded from epidemiological studies as they have been difficult to diagnose in electro-clinical terms )] TJ ET
0.267 0.267 0.267 rg
BT 562.724 479.263 Td /F4 8.7 Tf  [(1)] TJ ET
0.271 0.267 0.267 rg
BT 567.543 477.756 Td /F1 9.8 Tf  [( . )] TJ ET
BT 26.250 465.851 Td /F1 9.8 Tf  [(A recent study based on a UK birth cohort suggested an incidence of at least 1 in 40,000 live births for SCN1A positive Dravet )] TJ ET
BT 26.250 453.946 Td /F1 9.8 Tf  [(syndrome and 1 in 29.000 for Dravet syndrome as a whole )] TJ ET
0.267 0.267 0.267 rg
BT 282.031 455.453 Td /F4 8.7 Tf  [(2)] TJ ET
0.271 0.267 0.267 rg
BT 286.850 453.946 Td /F1 9.8 Tf  [( . Dravet syndrome has been misdiagnosed as whooping cough )] TJ ET
BT 26.250 442.041 Td /F1 9.8 Tf  [(vaccine damage or pertussis encephalopathy)] TJ ET
0.267 0.267 0.267 rg
BT 221.884 443.549 Td /F4 8.7 Tf  [(3)] TJ ET
0.271 0.267 0.267 rg
BT 226.702 442.041 Td /F1 9.8 Tf  [( .)] TJ ET
BT 26.250 422.637 Td /F1 9.8 Tf  [(Where the mutation is inherited the inheritance pattern is autosomal dominant but most cases are found to be de novo. Familial )] TJ ET
BT 26.250 410.732 Td /F1 9.8 Tf  [(cases most commonly arise in Genetic Epilepsy with Febrile Seizures plus \(GEFS+\). The majority of cases are sporadic and the )] TJ ET
BT 26.250 398.827 Td /F1 9.8 Tf  [(great value of this test is providing an early diagnosis and allowing appropriate treatment. Penetrance is difficult to estimate.)] TJ ET
BT 26.250 379.422 Td /F1 9.8 Tf  [(A confirmed diagnosis has implications for treatment stragegies and genetic counseling. It can save many additional costly and )] TJ ET
BT 26.250 367.518 Td /F1 9.8 Tf  [(invasive investigations. When a diagnosis confirms or supports a clinical suspicion, medication changes may result )] TJ ET
0.267 0.267 0.267 rg
BT 523.139 369.025 Td /F4 8.7 Tf  [(4)] TJ ET
0.271 0.267 0.267 rg
BT 527.958 367.518 Td /F1 9.8 Tf  [(. Anti-)] TJ ET
BT 26.250 355.613 Td /F1 9.8 Tf  [(epileptic medications such as carbamazepine, lamtrigine and pheytoin can worsen seizures in Dravets syndrome whereas there )] TJ ET
BT 26.250 343.708 Td /F1 9.8 Tf  [(is evidence from placebo controlled trials that a medication called stirpentol in combination with valproate and clobazam may )] TJ ET
BT 26.250 331.803 Td /F1 9.8 Tf  [(reduce seizures. Infants with Dravet syndrome suffer from developmental regression and there is good evidence that some of )] TJ ET
BT 26.250 319.899 Td /F1 9.8 Tf  [(this is due to uncontrolled seizures and abnormal EEG activity \(an epileptic encephalopathy\). There is clinical justification and )] TJ ET
BT 26.250 307.994 Td /F1 9.8 Tf  [(evidence from recent research on adults with the syndrome to hope that controlling seizures will reduce the cognitive )] TJ ET
BT 26.250 296.089 Td /F1 9.8 Tf  [(impairment associated with the syndrome )] TJ ET
0.267 0.267 0.267 rg
BT 208.312 297.596 Td /F4 8.7 Tf  [(5)] TJ ET
0.271 0.267 0.267 rg
BT 213.130 296.089 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 276.684 Td /F1 9.8 Tf  [(The clinical features of Dravet Syndrome develop over several years so without the support of molecular genetic testing the )] TJ ET
BT 26.250 264.780 Td /F1 9.8 Tf  [(diagnosis may not be made until 2-4 years of age. By this time the child may have suffered years of uncontrolled seizures and )] TJ ET
BT 26.250 252.875 Td /F1 9.8 Tf  [(already have significant cognitive impairment )] TJ ET
0.267 0.267 0.267 rg
BT 222.946 254.382 Td /F4 8.7 Tf  [(2)] TJ ET
0.271 0.267 0.267 rg
BT 227.765 252.875 Td /F1 9.8 Tf  [( .)] TJ ET
BT 26.250 216.272 Td /F4 12.0 Tf  [(Published Reviews, Recommendations and Guidelines)] TJ ET
BT 26.250 196.318 Td /F5 9.8 Tf  [(Systematic evidence reviews:)] TJ ET
BT 163.900 196.318 Td /F1 9.8 Tf  [( None identified)] TJ ET
BT 26.250 176.913 Td /F5 9.8 Tf  [(Recommendations by independent group:)] TJ ET
BT 221.815 176.913 Td /F1 9.8 Tf  [(UKGTN � Gene Dossier)] TJ ET
BT 26.250 157.509 Td /F5 9.8 Tf  [(Guidelines by professional groups:)] TJ ET
BT 189.875 157.509 Td /F1 9.8 Tf  [(None identified)] TJ ET
BT 26.250 120.906 Td /F4 12.0 Tf  [(Evidence overview)] TJ ET
BT 26.250 100.952 Td /F5 9.8 Tf  [(Analytic Validity)] TJ ET
BT 101.569 100.952 Td /F4 9.8 Tf  [(: )] TJ ET
BT 107.526 100.952 Td /F1 9.8 Tf  [(Test accuracy and reliability in measuring analytes or other entities measured \(analytic sensitivity and )] TJ ET
BT 26.250 89.047 Td /F1 9.8 Tf  [(specificity\).)] TJ ET
BT 26.250 69.642 Td /F1 9.8 Tf  [(Diagnostic testing methodologies:\(DNA sequencing\) Mutation scanning in single direction confirmed in opposite direction and )] TJ ET
BT 26.250 57.738 Td /F1 9.8 Tf  [(again in an exon specific separate assay. All primers are SNP and BLAST alignment checked. All mutations identified in a )] TJ ET
BT 26.250 45.833 Td /F1 9.8 Tf  [(previous preliminary project were confirmed using this methodology. This methodology is well established in the laboratory for )] TJ ET
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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

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0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F1 9.8 Tf  [(many disorders.)] TJ ET
BT 26.250 748.071 Td /F1 9.8 Tf  [(\(MLPA\) Use of an MLPA kit designed specifically for the SCN1A gene. Exon 21 deletion control identified amongst 10 normal )] TJ ET
BT 26.250 736.167 Td /F1 9.8 Tf  [(control samples, assay repeated to validate results. This methodology is well established in the laboratory for other disorders.)] TJ ET
BT 26.250 716.762 Td /F5 9.8 Tf  [(Validation)] TJ ET
BT 72.845 716.762 Td /F1 9.8 Tf  [(: Clinical Molecular Genetic Society \(CMGS\) Trainee project: 6/6 mutations were identified in �blind� analysis using )] TJ ET
BT 26.250 704.857 Td /F1 9.8 Tf  [(conformation sensitive capillary electrophoresis \(CSCE\). A further panel of 20 patients with varied infantile epileptic )] TJ ET
BT 26.250 692.952 Td /F1 9.8 Tf  [(encephalopathies, referred from a consultant paediatric neurologist, were screened using CSCE and DNA sequencing. Results )] TJ ET
BT 26.250 681.048 Td /F1 9.8 Tf  [(were confirmed by bi-directional sequencing.)] TJ ET
BT 26.250 661.643 Td /F5 9.8 Tf  [(Analytical Sensitivity)] TJ ET
BT 123.789 661.643 Td /F1 9.8 Tf  [(is estimated at >98% for bi-directional sequencing, 99.5% when MLPA included based upon our own )] TJ ET
BT 26.250 649.738 Td /F1 9.8 Tf  [(laboratory test performance experience.)] TJ ET
BT 26.250 630.333 Td /F5 9.8 Tf  [(Clinical Validity)] TJ ET
BT 98.322 630.333 Td /F4 9.8 Tf  [(: )] TJ ET
BT 104.279 630.333 Td /F1 9.8 Tf  [(Test accuracy and reliability in)] TJ ET
BT 234.861 630.333 Td /F6 9.8 Tf  [( supporting clinical or public health assessment)] TJ ET
BT 438.607 630.333 Td /F6 9.8 Tf  [(.)] TJ ET
BT 26.250 610.929 Td /F1 9.8 Tf  [(In all Dravet syndrome cases the clinical sensitivity is around 80%, rising to 90% in typical Dravet syndrome cases. In our series )] TJ ET
BT 26.250 599.024 Td /F1 9.8 Tf  [(about 10% of individuals classified as typical Dravet syndrome were not found to have an SCN1A mutation.)] TJ ET
BT 26.250 579.619 Td /F1 9.8 Tf  [(The negative predictive value is estimated to be low. Approximately 1/100 of our patients thought to have SMEI/related )] TJ ET
BT 26.250 567.714 Td /F1 9.8 Tf  [(syndrome \(based on clinical, and electro-clinical data\) were found not to have an SCN1A mutation. This is most likely to be due )] TJ ET
BT 26.250 555.810 Td /F1 9.8 Tf  [(to allelic heterogeneity particularly for the related syndromes.)] TJ ET
BT 26.250 536.405 Td /F1 9.8 Tf  [(The negative predictive value is estimated to be low. Approximately 1/100 of our patients thought to have SMEI/related )] TJ ET
BT 26.250 524.500 Td /F1 9.8 Tf  [(syndrome \(based on clinical, and electro-clinical data\) were found not to have an SCN1A mutation. this is most likely to be due )] TJ ET
BT 26.250 512.595 Td /F1 9.8 Tf  [(to allelic heterogeneity particularly for the related syndromes.)] TJ ET
BT 26.250 475.993 Td /F4 12.0 Tf  [(Clinical Utility: Net benefit of test in improving health outcomes)] TJ ET
BT 26.250 456.039 Td /F1 9.8 Tf  [(When a pathogenic mutation is identified the diagnosis can be made and/or confirmed \(i.e. some patients are so young that )] TJ ET
BT 26.250 444.134 Td /F1 9.8 Tf  [(their epilepsy phenotype has not fully evolved enough for a clinical diagnosis to be made\). A confirmed diagnosis has )] TJ ET
BT 26.250 432.229 Td /F1 9.8 Tf  [(implications for treatment strategies and genetic counselling. It can save many additional costly and invasive investigations. )] TJ ET
BT 26.250 420.324 Td /F1 9.8 Tf  [(When a genetic diagnosis confirms or supports a clinical suspicion, medication changes may result. Anti-epileptic medications )] TJ ET
BT 26.250 408.420 Td /F1 9.8 Tf  [(such as carbamazepine, lamotrigine and phenytoin can worsen seizures in Dravet Syndrome whereas there is evidence from )] TJ ET
BT 26.250 396.515 Td /F1 9.8 Tf  [(placebo controlled trials that a medication called stiripentol in combination with valproate and clobazam may reduce seizures. )] TJ ET
BT 26.250 384.610 Td /F1 9.8 Tf  [(Infants with Dravet syndrome suffer from developmental regression and there is good evidence that some of this is due to the )] TJ ET
BT 26.250 372.705 Td /F1 9.8 Tf  [(uncontrolled seizures and abnormal EEG activity \(an epileptic encephalopathy\). There is clinical justification and evidence from )] TJ ET
BT 26.250 360.801 Td /F1 9.8 Tf  [(recent research on adults with the syndrome to hope that controlling seizures will reduce the cognitive impairment associated )] TJ ET
BT 26.250 348.896 Td /F1 9.8 Tf  [(with the syndrome )] TJ ET
0.267 0.267 0.267 rg
BT 108.072 350.403 Td /F4 8.7 Tf  [(5)] TJ ET
0.271 0.267 0.267 rg
BT 112.891 348.896 Td /F1 9.8 Tf  [( .)] TJ ET
BT 26.250 329.491 Td /F1 9.8 Tf  [(We undertook a review of our service using questionnaires to ask carers and physicians their views on genetic testing. 187 )] TJ ET
BT 26.250 317.586 Td /F1 9.8 Tf  [(carers and 163 physicians responded.)] TJ ET
BT 26.250 298.182 Td /F1 9.8 Tf  [(In the carers of the mutation positive group, 87% reported genetic testing helpful, 55% said it led to a change in treatment )] TJ ET
BT 26.250 286.277 Td /F1 9.8 Tf  [(resulting in fewer seizures. 41% described other changes including improved access to therapies and respite care. In 48%, )] TJ ET
BT 26.250 274.372 Td /F1 9.8 Tf  [(physicians reported that testing facilitated diagnosis earlier than with clinical and EEG data alone. Molecular testing prevented )] TJ ET
BT 26.250 262.467 Td /F1 9.8 Tf  [(additional investigations in 67% of cases, altered treatment approach in 69%, helped medication choice in 74% and through )] TJ ET
BT 26.250 250.563 Td /F1 9.8 Tf  [(medication change improved seizure control in 42%. Carer and physician views correlated significantly with regard to the clinical )] TJ ET
BT 26.250 238.658 Td /F1 9.8 Tf  [(utility of genetic testing. In addition to confirming a clinical diagnosis, SCN1A genetic testing enabled early diagnosis, influenced )] TJ ET
BT 26.250 226.753 Td /F1 9.8 Tf  [(treatment-choice and facilitated access to additional therapies in a significant proportion of cases)] TJ ET
0.267 0.267 0.267 rg
BT 442.985 228.260 Td /F4 8.7 Tf  [(4)] TJ ET
0.271 0.267 0.267 rg
BT 447.803 226.753 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 207.348 Td /F1 9.8 Tf  [(UKGTN Testing Criteria: Minimum criteria required for testing to be appropriate as stated in the Gene Dossier.)] TJ ET
BT 26.250 187.944 Td /F1 9.8 Tf  [(Electroclinical Phenotype of Dravet Syndrome or clinical subtypes � several seizure types in one individual with onset in infancy, )] TJ ET
BT 26.250 176.039 Td /F1 9.8 Tf  [(refractory to medication and with generalised spike and wave on EEG OR Infants less than 1 year with 2 or more prolonged )] TJ ET
BT 26.250 164.134 Td /F1 9.8 Tf  [(hemiclonic febrile seizures in early infancy)] TJ ET
BT 26.250 127.532 Td /F4 12.0 Tf  [(Links)] TJ ET
0.271 0.267 0.267 RG
40.337 110.545 m 
40.337 110.992 40.154 111.436 39.838 111.752 c
39.522 112.067 39.078 112.251 38.631 112.251 c
38.185 112.251 37.741 112.067 37.425 111.752 c
37.109 111.436 36.925 110.992 36.925 110.545 c
36.925 110.098 37.109 109.654 37.425 109.338 c
37.741 109.023 38.185 108.839 38.631 108.839 c
39.078 108.839 39.522 109.023 39.838 109.338 c
40.154 109.654 40.337 110.098 40.337 110.545 c f
BT 45.750 107.577 Td /F1 9.8 Tf  [(UKGTN Homepage: https://www.ukgtn.nhs.uk/gtn/Home)] TJ ET
40.337 94.890 m 
40.337 95.337 40.154 95.781 39.838 96.097 c
39.522 96.413 39.078 96.596 38.631 96.596 c
38.185 96.596 37.741 96.413 37.425 96.097 c
37.109 95.781 36.925 95.337 36.925 94.890 c
36.925 94.444 37.109 94.000 37.425 93.684 c
37.741 93.368 38.185 93.184 38.631 93.184 c
39.078 93.184 39.522 93.368 39.838 93.684 c
40.154 94.000 40.337 94.444 40.337 94.890 c f
BT 45.750 91.923 Td /F1 9.8 Tf  [(UKGTN Gene Dossier: https://www.ukgtn.nhs.uk/gtn/Information/Services/Gene+Dossiers)] TJ ET
40.337 79.235 m 
40.337 79.682 40.154 80.126 39.838 80.442 c
39.522 80.758 39.078 80.942 38.631 80.942 c
38.185 80.942 37.741 80.758 37.425 80.442 c
37.109 80.126 36.925 79.682 36.925 79.235 c
36.925 78.789 37.109 78.345 37.425 78.029 c
37.741 77.713 38.185 77.529 38.631 77.529 c
39.078 77.529 39.522 77.713 39.838 78.029 c
40.154 78.345 40.337 78.789 40.337 79.235 c f
BT 45.750 76.268 Td /F1 9.8 Tf  [(UKGTN Testing criteria: https://www.ukgtn.nhs.uk/gtn/Information/Services/Testing_Criteria;)] TJ ET
40.337 63.581 m 
40.337 64.027 40.154 64.471 39.838 64.787 c
39.522 65.103 39.078 65.287 38.631 65.287 c
38.185 65.287 37.741 65.103 37.425 64.787 c
37.109 64.471 36.925 64.027 36.925 63.581 c
36.925 63.134 37.109 62.690 37.425 62.374 c
37.741 62.058 38.185 61.874 38.631 61.874 c
39.078 61.874 39.522 62.058 39.838 62.374 c
40.154 62.690 40.337 63.134 40.337 63.581 c f
BT 45.750 60.613 Td /F1 9.8 Tf  [(GeneReviews: https://www.ukgtn.nhs.uk/gtn/Search+for+a+Test/Search+by+Disease+or+Gene)] TJ ET
Q
q
15.000 46.982 577.500 730.018 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F1 9.8 Tf  [(many disorders.)] TJ ET
BT 26.250 748.071 Td /F1 9.8 Tf  [(\(MLPA\) Use of an MLPA kit designed specifically for the SCN1A gene. Exon 21 deletion control identified amongst 10 normal )] TJ ET
BT 26.250 736.167 Td /F1 9.8 Tf  [(control samples, assay repeated to validate results. This methodology is well established in the laboratory for other disorders.)] TJ ET
BT 26.250 716.762 Td /F5 9.8 Tf  [(Validation)] TJ ET
BT 72.845 716.762 Td /F1 9.8 Tf  [(: Clinical Molecular Genetic Society \(CMGS\) Trainee project: 6/6 mutations were identified in �blind� analysis using )] TJ ET
BT 26.250 704.857 Td /F1 9.8 Tf  [(conformation sensitive capillary electrophoresis \(CSCE\). A further panel of 20 patients with varied infantile epileptic )] TJ ET
BT 26.250 692.952 Td /F1 9.8 Tf  [(encephalopathies, referred from a consultant paediatric neurologist, were screened using CSCE and DNA sequencing. Results )] TJ ET
BT 26.250 681.048 Td /F1 9.8 Tf  [(were confirmed by bi-directional sequencing.)] TJ ET
BT 26.250 661.643 Td /F5 9.8 Tf  [(Analytical Sensitivity)] TJ ET
BT 123.789 661.643 Td /F1 9.8 Tf  [(is estimated at >98% for bi-directional sequencing, 99.5% when MLPA included based upon our own )] TJ ET
BT 26.250 649.738 Td /F1 9.8 Tf  [(laboratory test performance experience.)] TJ ET
BT 26.250 630.333 Td /F5 9.8 Tf  [(Clinical Validity)] TJ ET
BT 98.322 630.333 Td /F4 9.8 Tf  [(: )] TJ ET
BT 104.279 630.333 Td /F1 9.8 Tf  [(Test accuracy and reliability in)] TJ ET
BT 234.861 630.333 Td /F6 9.8 Tf  [( supporting clinical or public health assessment)] TJ ET
BT 438.607 630.333 Td /F6 9.8 Tf  [(.)] TJ ET
BT 26.250 610.929 Td /F1 9.8 Tf  [(In all Dravet syndrome cases the clinical sensitivity is around 80%, rising to 90% in typical Dravet syndrome cases. In our series )] TJ ET
BT 26.250 599.024 Td /F1 9.8 Tf  [(about 10% of individuals classified as typical Dravet syndrome were not found to have an SCN1A mutation.)] TJ ET
BT 26.250 579.619 Td /F1 9.8 Tf  [(The negative predictive value is estimated to be low. Approximately 1/100 of our patients thought to have SMEI/related )] TJ ET
BT 26.250 567.714 Td /F1 9.8 Tf  [(syndrome \(based on clinical, and electro-clinical data\) were found not to have an SCN1A mutation. This is most likely to be due )] TJ ET
BT 26.250 555.810 Td /F1 9.8 Tf  [(to allelic heterogeneity particularly for the related syndromes.)] TJ ET
BT 26.250 536.405 Td /F1 9.8 Tf  [(The negative predictive value is estimated to be low. Approximately 1/100 of our patients thought to have SMEI/related )] TJ ET
BT 26.250 524.500 Td /F1 9.8 Tf  [(syndrome \(based on clinical, and electro-clinical data\) were found not to have an SCN1A mutation. this is most likely to be due )] TJ ET
BT 26.250 512.595 Td /F1 9.8 Tf  [(to allelic heterogeneity particularly for the related syndromes.)] TJ ET
BT 26.250 475.993 Td /F4 12.0 Tf  [(Clinical Utility: Net benefit of test in improving health outcomes)] TJ ET
BT 26.250 456.039 Td /F1 9.8 Tf  [(When a pathogenic mutation is identified the diagnosis can be made and/or confirmed \(i.e. some patients are so young that )] TJ ET
BT 26.250 444.134 Td /F1 9.8 Tf  [(their epilepsy phenotype has not fully evolved enough for a clinical diagnosis to be made\). A confirmed diagnosis has )] TJ ET
BT 26.250 432.229 Td /F1 9.8 Tf  [(implications for treatment strategies and genetic counselling. It can save many additional costly and invasive investigations. )] TJ ET
BT 26.250 420.324 Td /F1 9.8 Tf  [(When a genetic diagnosis confirms or supports a clinical suspicion, medication changes may result. Anti-epileptic medications )] TJ ET
BT 26.250 408.420 Td /F1 9.8 Tf  [(such as carbamazepine, lamotrigine and phenytoin can worsen seizures in Dravet Syndrome whereas there is evidence from )] TJ ET
BT 26.250 396.515 Td /F1 9.8 Tf  [(placebo controlled trials that a medication called stiripentol in combination with valproate and clobazam may reduce seizures. )] TJ ET
BT 26.250 384.610 Td /F1 9.8 Tf  [(Infants with Dravet syndrome suffer from developmental regression and there is good evidence that some of this is due to the )] TJ ET
BT 26.250 372.705 Td /F1 9.8 Tf  [(uncontrolled seizures and abnormal EEG activity \(an epileptic encephalopathy\). There is clinical justification and evidence from )] TJ ET
BT 26.250 360.801 Td /F1 9.8 Tf  [(recent research on adults with the syndrome to hope that controlling seizures will reduce the cognitive impairment associated )] TJ ET
BT 26.250 348.896 Td /F1 9.8 Tf  [(with the syndrome )] TJ ET
0.267 0.267 0.267 rg
BT 108.072 350.403 Td /F4 8.7 Tf  [(5)] TJ ET
0.271 0.267 0.267 rg
BT 112.891 348.896 Td /F1 9.8 Tf  [( .)] TJ ET
BT 26.250 329.491 Td /F1 9.8 Tf  [(We undertook a review of our service using questionnaires to ask carers and physicians their views on genetic testing. 187 )] TJ ET
BT 26.250 317.586 Td /F1 9.8 Tf  [(carers and 163 physicians responded.)] TJ ET
BT 26.250 298.182 Td /F1 9.8 Tf  [(In the carers of the mutation positive group, 87% reported genetic testing helpful, 55% said it led to a change in treatment )] TJ ET
BT 26.250 286.277 Td /F1 9.8 Tf  [(resulting in fewer seizures. 41% described other changes including improved access to therapies and respite care. In 48%, )] TJ ET
BT 26.250 274.372 Td /F1 9.8 Tf  [(physicians reported that testing facilitated diagnosis earlier than with clinical and EEG data alone. Molecular testing prevented )] TJ ET
BT 26.250 262.467 Td /F1 9.8 Tf  [(additional investigations in 67% of cases, altered treatment approach in 69%, helped medication choice in 74% and through )] TJ ET
BT 26.250 250.563 Td /F1 9.8 Tf  [(medication change improved seizure control in 42%. Carer and physician views correlated significantly with regard to the clinical )] TJ ET
BT 26.250 238.658 Td /F1 9.8 Tf  [(utility of genetic testing. In addition to confirming a clinical diagnosis, SCN1A genetic testing enabled early diagnosis, influenced )] TJ ET
BT 26.250 226.753 Td /F1 9.8 Tf  [(treatment-choice and facilitated access to additional therapies in a significant proportion of cases)] TJ ET
0.267 0.267 0.267 rg
BT 442.985 228.260 Td /F4 8.7 Tf  [(4)] TJ ET
0.271 0.267 0.267 rg
BT 447.803 226.753 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 207.348 Td /F1 9.8 Tf  [(UKGTN Testing Criteria: Minimum criteria required for testing to be appropriate as stated in the Gene Dossier.)] TJ ET
BT 26.250 187.944 Td /F1 9.8 Tf  [(Electroclinical Phenotype of Dravet Syndrome or clinical subtypes � several seizure types in one individual with onset in infancy, )] TJ ET
BT 26.250 176.039 Td /F1 9.8 Tf  [(refractory to medication and with generalised spike and wave on EEG OR Infants less than 1 year with 2 or more prolonged )] TJ ET
BT 26.250 164.134 Td /F1 9.8 Tf  [(hemiclonic febrile seizures in early infancy)] TJ ET
BT 26.250 127.532 Td /F4 12.0 Tf  [(Links)] TJ ET
0.271 0.267 0.267 RG
40.337 110.545 m 
40.337 110.992 40.154 111.436 39.838 111.752 c
39.522 112.067 39.078 112.251 38.631 112.251 c
38.185 112.251 37.741 112.067 37.425 111.752 c
37.109 111.436 36.925 110.992 36.925 110.545 c
36.925 110.098 37.109 109.654 37.425 109.338 c
37.741 109.023 38.185 108.839 38.631 108.839 c
39.078 108.839 39.522 109.023 39.838 109.338 c
40.154 109.654 40.337 110.098 40.337 110.545 c f
BT 45.750 107.577 Td /F1 9.8 Tf  [(UKGTN Homepage: https://www.ukgtn.nhs.uk/gtn/Home)] TJ ET
40.337 94.890 m 
40.337 95.337 40.154 95.781 39.838 96.097 c
39.522 96.413 39.078 96.596 38.631 96.596 c
38.185 96.596 37.741 96.413 37.425 96.097 c
37.109 95.781 36.925 95.337 36.925 94.890 c
36.925 94.444 37.109 94.000 37.425 93.684 c
37.741 93.368 38.185 93.184 38.631 93.184 c
39.078 93.184 39.522 93.368 39.838 93.684 c
40.154 94.000 40.337 94.444 40.337 94.890 c f
BT 45.750 91.923 Td /F1 9.8 Tf  [(UKGTN Gene Dossier: https://www.ukgtn.nhs.uk/gtn/Information/Services/Gene+Dossiers)] TJ ET
40.337 79.235 m 
40.337 79.682 40.154 80.126 39.838 80.442 c
39.522 80.758 39.078 80.942 38.631 80.942 c
38.185 80.942 37.741 80.758 37.425 80.442 c
37.109 80.126 36.925 79.682 36.925 79.235 c
36.925 78.789 37.109 78.345 37.425 78.029 c
37.741 77.713 38.185 77.529 38.631 77.529 c
39.078 77.529 39.522 77.713 39.838 78.029 c
40.154 78.345 40.337 78.789 40.337 79.235 c f
BT 45.750 76.268 Td /F1 9.8 Tf  [(UKGTN Testing criteria: https://www.ukgtn.nhs.uk/gtn/Information/Services/Testing_Criteria;)] TJ ET
40.337 63.581 m 
40.337 64.027 40.154 64.471 39.838 64.787 c
39.522 65.103 39.078 65.287 38.631 65.287 c
38.185 65.287 37.741 65.103 37.425 64.787 c
37.109 64.471 36.925 64.027 36.925 63.581 c
36.925 63.134 37.109 62.690 37.425 62.374 c
37.741 62.058 38.185 61.874 38.631 61.874 c
39.078 61.874 39.522 62.058 39.838 62.374 c
40.154 62.690 40.337 63.134 40.337 63.581 c f
BT 45.750 60.613 Td /F1 9.8 Tf  [(GeneReviews: https://www.ukgtn.nhs.uk/gtn/Search+for+a+Test/Search+by+Disease+or+Gene)] TJ ET
Q
q
15.000 46.982 577.500 730.018 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F1 9.8 Tf  [(many disorders.)] TJ ET
BT 26.250 748.071 Td /F1 9.8 Tf  [(\(MLPA\) Use of an MLPA kit designed specifically for the SCN1A gene. Exon 21 deletion control identified amongst 10 normal )] TJ ET
BT 26.250 736.167 Td /F1 9.8 Tf  [(control samples, assay repeated to validate results. This methodology is well established in the laboratory for other disorders.)] TJ ET
BT 26.250 716.762 Td /F5 9.8 Tf  [(Validation)] TJ ET
BT 72.845 716.762 Td /F1 9.8 Tf  [(: Clinical Molecular Genetic Society \(CMGS\) Trainee project: 6/6 mutations were identified in �blind� analysis using )] TJ ET
BT 26.250 704.857 Td /F1 9.8 Tf  [(conformation sensitive capillary electrophoresis \(CSCE\). A further panel of 20 patients with varied infantile epileptic )] TJ ET
BT 26.250 692.952 Td /F1 9.8 Tf  [(encephalopathies, referred from a consultant paediatric neurologist, were screened using CSCE and DNA sequencing. Results )] TJ ET
BT 26.250 681.048 Td /F1 9.8 Tf  [(were confirmed by bi-directional sequencing.)] TJ ET
BT 26.250 661.643 Td /F5 9.8 Tf  [(Analytical Sensitivity)] TJ ET
BT 123.789 661.643 Td /F1 9.8 Tf  [(is estimated at >98% for bi-directional sequencing, 99.5% when MLPA included based upon our own )] TJ ET
BT 26.250 649.738 Td /F1 9.8 Tf  [(laboratory test performance experience.)] TJ ET
BT 26.250 630.333 Td /F5 9.8 Tf  [(Clinical Validity)] TJ ET
BT 98.322 630.333 Td /F4 9.8 Tf  [(: )] TJ ET
BT 104.279 630.333 Td /F1 9.8 Tf  [(Test accuracy and reliability in)] TJ ET
BT 234.861 630.333 Td /F6 9.8 Tf  [( supporting clinical or public health assessment)] TJ ET
BT 438.607 630.333 Td /F6 9.8 Tf  [(.)] TJ ET
BT 26.250 610.929 Td /F1 9.8 Tf  [(In all Dravet syndrome cases the clinical sensitivity is around 80%, rising to 90% in typical Dravet syndrome cases. In our series )] TJ ET
BT 26.250 599.024 Td /F1 9.8 Tf  [(about 10% of individuals classified as typical Dravet syndrome were not found to have an SCN1A mutation.)] TJ ET
BT 26.250 579.619 Td /F1 9.8 Tf  [(The negative predictive value is estimated to be low. Approximately 1/100 of our patients thought to have SMEI/related )] TJ ET
BT 26.250 567.714 Td /F1 9.8 Tf  [(syndrome \(based on clinical, and electro-clinical data\) were found not to have an SCN1A mutation. This is most likely to be due )] TJ ET
BT 26.250 555.810 Td /F1 9.8 Tf  [(to allelic heterogeneity particularly for the related syndromes.)] TJ ET
BT 26.250 536.405 Td /F1 9.8 Tf  [(The negative predictive value is estimated to be low. Approximately 1/100 of our patients thought to have SMEI/related )] TJ ET
BT 26.250 524.500 Td /F1 9.8 Tf  [(syndrome \(based on clinical, and electro-clinical data\) were found not to have an SCN1A mutation. this is most likely to be due )] TJ ET
BT 26.250 512.595 Td /F1 9.8 Tf  [(to allelic heterogeneity particularly for the related syndromes.)] TJ ET
BT 26.250 475.993 Td /F4 12.0 Tf  [(Clinical Utility: Net benefit of test in improving health outcomes)] TJ ET
BT 26.250 456.039 Td /F1 9.8 Tf  [(When a pathogenic mutation is identified the diagnosis can be made and/or confirmed \(i.e. some patients are so young that )] TJ ET
BT 26.250 444.134 Td /F1 9.8 Tf  [(their epilepsy phenotype has not fully evolved enough for a clinical diagnosis to be made\). A confirmed diagnosis has )] TJ ET
BT 26.250 432.229 Td /F1 9.8 Tf  [(implications for treatment strategies and genetic counselling. It can save many additional costly and invasive investigations. )] TJ ET
BT 26.250 420.324 Td /F1 9.8 Tf  [(When a genetic diagnosis confirms or supports a clinical suspicion, medication changes may result. Anti-epileptic medications )] TJ ET
BT 26.250 408.420 Td /F1 9.8 Tf  [(such as carbamazepine, lamotrigine and phenytoin can worsen seizures in Dravet Syndrome whereas there is evidence from )] TJ ET
BT 26.250 396.515 Td /F1 9.8 Tf  [(placebo controlled trials that a medication called stiripentol in combination with valproate and clobazam may reduce seizures. )] TJ ET
BT 26.250 384.610 Td /F1 9.8 Tf  [(Infants with Dravet syndrome suffer from developmental regression and there is good evidence that some of this is due to the )] TJ ET
BT 26.250 372.705 Td /F1 9.8 Tf  [(uncontrolled seizures and abnormal EEG activity \(an epileptic encephalopathy\). There is clinical justification and evidence from )] TJ ET
BT 26.250 360.801 Td /F1 9.8 Tf  [(recent research on adults with the syndrome to hope that controlling seizures will reduce the cognitive impairment associated )] TJ ET
BT 26.250 348.896 Td /F1 9.8 Tf  [(with the syndrome )] TJ ET
0.267 0.267 0.267 rg
BT 108.072 350.403 Td /F4 8.7 Tf  [(5)] TJ ET
0.271 0.267 0.267 rg
BT 112.891 348.896 Td /F1 9.8 Tf  [( .)] TJ ET
BT 26.250 329.491 Td /F1 9.8 Tf  [(We undertook a review of our service using questionnaires to ask carers and physicians their views on genetic testing. 187 )] TJ ET
BT 26.250 317.586 Td /F1 9.8 Tf  [(carers and 163 physicians responded.)] TJ ET
BT 26.250 298.182 Td /F1 9.8 Tf  [(In the carers of the mutation positive group, 87% reported genetic testing helpful, 55% said it led to a change in treatment )] TJ ET
BT 26.250 286.277 Td /F1 9.8 Tf  [(resulting in fewer seizures. 41% described other changes including improved access to therapies and respite care. In 48%, )] TJ ET
BT 26.250 274.372 Td /F1 9.8 Tf  [(physicians reported that testing facilitated diagnosis earlier than with clinical and EEG data alone. Molecular testing prevented )] TJ ET
BT 26.250 262.467 Td /F1 9.8 Tf  [(additional investigations in 67% of cases, altered treatment approach in 69%, helped medication choice in 74% and through )] TJ ET
BT 26.250 250.563 Td /F1 9.8 Tf  [(medication change improved seizure control in 42%. Carer and physician views correlated significantly with regard to the clinical )] TJ ET
BT 26.250 238.658 Td /F1 9.8 Tf  [(utility of genetic testing. In addition to confirming a clinical diagnosis, SCN1A genetic testing enabled early diagnosis, influenced )] TJ ET
BT 26.250 226.753 Td /F1 9.8 Tf  [(treatment-choice and facilitated access to additional therapies in a significant proportion of cases)] TJ ET
0.267 0.267 0.267 rg
BT 442.985 228.260 Td /F4 8.7 Tf  [(4)] TJ ET
0.271 0.267 0.267 rg
BT 447.803 226.753 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 207.348 Td /F1 9.8 Tf  [(UKGTN Testing Criteria: Minimum criteria required for testing to be appropriate as stated in the Gene Dossier.)] TJ ET
BT 26.250 187.944 Td /F1 9.8 Tf  [(Electroclinical Phenotype of Dravet Syndrome or clinical subtypes � several seizure types in one individual with onset in infancy, )] TJ ET
BT 26.250 176.039 Td /F1 9.8 Tf  [(refractory to medication and with generalised spike and wave on EEG OR Infants less than 1 year with 2 or more prolonged )] TJ ET
BT 26.250 164.134 Td /F1 9.8 Tf  [(hemiclonic febrile seizures in early infancy)] TJ ET
BT 26.250 127.532 Td /F4 12.0 Tf  [(Links)] TJ ET
0.271 0.267 0.267 RG
40.337 110.545 m 
40.337 110.992 40.154 111.436 39.838 111.752 c
39.522 112.067 39.078 112.251 38.631 112.251 c
38.185 112.251 37.741 112.067 37.425 111.752 c
37.109 111.436 36.925 110.992 36.925 110.545 c
36.925 110.098 37.109 109.654 37.425 109.338 c
37.741 109.023 38.185 108.839 38.631 108.839 c
39.078 108.839 39.522 109.023 39.838 109.338 c
40.154 109.654 40.337 110.098 40.337 110.545 c f
BT 45.750 107.577 Td /F1 9.8 Tf  [(UKGTN Homepage: https://www.ukgtn.nhs.uk/gtn/Home)] TJ ET
40.337 94.890 m 
40.337 95.337 40.154 95.781 39.838 96.097 c
39.522 96.413 39.078 96.596 38.631 96.596 c
38.185 96.596 37.741 96.413 37.425 96.097 c
37.109 95.781 36.925 95.337 36.925 94.890 c
36.925 94.444 37.109 94.000 37.425 93.684 c
37.741 93.368 38.185 93.184 38.631 93.184 c
39.078 93.184 39.522 93.368 39.838 93.684 c
40.154 94.000 40.337 94.444 40.337 94.890 c f
BT 45.750 91.923 Td /F1 9.8 Tf  [(UKGTN Gene Dossier: https://www.ukgtn.nhs.uk/gtn/Information/Services/Gene+Dossiers)] TJ ET
40.337 79.235 m 
40.337 79.682 40.154 80.126 39.838 80.442 c
39.522 80.758 39.078 80.942 38.631 80.942 c
38.185 80.942 37.741 80.758 37.425 80.442 c
37.109 80.126 36.925 79.682 36.925 79.235 c
36.925 78.789 37.109 78.345 37.425 78.029 c
37.741 77.713 38.185 77.529 38.631 77.529 c
39.078 77.529 39.522 77.713 39.838 78.029 c
40.154 78.345 40.337 78.789 40.337 79.235 c f
BT 45.750 76.268 Td /F1 9.8 Tf  [(UKGTN Testing criteria: https://www.ukgtn.nhs.uk/gtn/Information/Services/Testing_Criteria;)] TJ ET
40.337 63.581 m 
40.337 64.027 40.154 64.471 39.838 64.787 c
39.522 65.103 39.078 65.287 38.631 65.287 c
38.185 65.287 37.741 65.103 37.425 64.787 c
37.109 64.471 36.925 64.027 36.925 63.581 c
36.925 63.134 37.109 62.690 37.425 62.374 c
37.741 62.058 38.185 61.874 38.631 61.874 c
39.078 61.874 39.522 62.058 39.838 62.374 c
40.154 62.690 40.337 63.134 40.337 63.581 c f
BT 45.750 60.613 Td /F1 9.8 Tf  [(GeneReviews: https://www.ukgtn.nhs.uk/gtn/Search+for+a+Test/Search+by+Disease+or+Gene)] 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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