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 organization: Neuroscience Center
Research Programs Unit
Anna-Elina Lehesjoki / Principal Investigator
Research Programme for Molecular Neurology
Institute for Molecular Medicine Finland
Aarno Palotie / Principal Investigator
Genomics of Neurological and Neuropsychiatric Disorders
Date: 2016-03-18
Language: eng
Number of pages: 14
Belongs to series: PLoS One
ISSN: 1932-6203
DOI: https://doi.org/10.1371/journal.pone.0150426
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.
Description: A. Palotie on työryhmän jäsen.
3112 Neurosciences
3111 Biomedicine
Peer reviewed: Yes
Usage restriction: openAccess
Self-archived version: publishedVersion

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