Evaluation of Presumably Disease Causing SCN1A Variants in a Cohort of Common Epilepsy Syndromes

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Lal , D , Reinthaler , E M , Dejanovici , B , May , P , Thiele , H , Lehesjoki , A-E , Schwarz , G , Riesch , E , Ikram , M A , van Duijn , C M , Uitterlinden , A G , Hofman , A , Steinboeck , H , Gruber-Sedlmayr , U , Neophytou , B , Zara , F , Hahn , A , Gormley , P , Becker , F , Weber , Y G , Cilio , M R , Kunz , W S , Krause , R , Zimprich , F , Lemke , J R , Nuernberg , P , Sander , T , Lerche , H , Neubauer , B A , Genetic Comm Italian League Agains , EuroEPINOMICS CoGIE Consortium & Palotie , A 2016 , ' Evaluation of Presumably Disease Causing SCN1A Variants in a Cohort of Common Epilepsy Syndromes ' , PLoS One , vol. 11 , no. 3 , 0150426 . https://doi.org/10.1371/journal.pone.0150426

Title: Evaluation of Presumably Disease Causing SCN1A Variants in a Cohort of Common Epilepsy Syndromes
Author: Lal, Dennis; Reinthaler, Eva M.; Dejanovici, Borislav; May, Patrick; Thiele, Holger; Lehesjoki, Anna-Elina; Schwarz, Gunter; Riesch, Erik; Ikram, M. Arfan; van Duijn, Cornelia M.; Uitterlinden, Andre G.; Hofman, Albert; Steinboeck, Hannelore; Gruber-Sedlmayr, Ursula; Neophytou, Birgit; Zara, Federico; Hahn, Andreas; Gormley, Padhraig; Becker, Felicitas; Weber, Yvonne G.; Cilio, Maria Roberta; Kunz, Wolfram S.; Krause, Roland; Zimprich, Fritz; Lemke, Johannes R.; Nuernberg, Peter; Sander, Thomas; Lerche, Holger; Neubauer, Bernd A.; Genetic Comm Italian League Agains; EuroEPINOMICS CoGIE Consortium; Palotie, Aarno
Contributor: University of Helsinki, Neuroscience Center
University of Helsinki, Institute for Molecular Medicine Finland
Date: 2016-03-18
Language: eng
Number of pages: 14
Belongs to series: PLoS One
ISSN: 1932-6203
URI: http://hdl.handle.net/10138/161347
Abstract: Objective The SCN1A gene, coding for the voltage-gated Na+ channel alpha subunit NaV1.1, is the clinically most relevant epilepsy gene. With the advent of high-throughput next-generation sequencing, clinical laboratories are generating an ever-increasing catalogue of SCN1A variants. Variants are more likely to be classified as pathogenic if they have already been identified previously in a patient with epilepsy. Here, we critically re-evaluate the pathogenicity of this class of variants in a cohort of patients with common epilepsy syndromes and subsequently ask whether a significant fraction of benign variants have been misclassified as pathogenic. Methods We screened a discovery cohort of 448 patients with a broad range of common genetic epilepsies and 734 controls for previously reported SCN1A mutations that were assumed to be disease causing. We re-evaluated the evidence for pathogenicity of the identified variants using in silico predictions, segregation, original reports, available functional data and assessment of allele frequencies in healthy individuals as well as in a follow up cohort of 777 patients. Results and Interpretation We identified 8 known missense mutations, previously reported as pathogenic, in a total of 17 unrelated epilepsy patients (17/448; 3.80%). Our re-evaluation indicates that 7 out of these 8 variants (p.R27T; p.R28C; p.R542Q; p.R604H; p.T1250M; p.E1308D; p.R1928G; NP_001159435.1) are not pathogenic. Only the p. T1174S mutation may be considered as a genetic risk factor for epilepsy of small effect size based on the enrichment in patients (P = 6.60 x 10(-4); OR = 0.32, fishers exact test), previous functional studies but incomplete penetrance. Thus, incorporation of previous studies in genetic counseling of SCN1A sequencing results is challenging and may produce incorrect conclusions.
Subject: FEBRILE SEIZURES PLUS
NEURONAL SODIUM-CHANNEL
SEVERE MYOCLONIC EPILEPSY
GENERALIZED EPILEPSY
DRAVET SYNDROME
HEMIPLEGIC MIGRAINE
ITALIAN PATIENTS
MUTATION
GENE
PREVALENCE
3112 Neurosciences
3111 Biomedicine
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