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Evaluation of presumably disease causing SCN1A variants in a cohort of common epilepsy syndromes

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Item Type:Article
Title:Evaluation of presumably disease causing SCN1A variants in a cohort of common epilepsy syndromes
Creators Name:Lal, D. and Reinthaler, E.M. and Dejanovic, B. and May, P. and Thiele, H. and Lehesjoki, A.E. and Schwarz, G. and Riesch, E. and Ikram, M.A. and van Duijn, C.M. and Uitterlinden, A.G. and Hofman, A. and Steinböck, H. and Gruber-Sedlmayr, U. and Neophytou, B. and Zara, F. and Hahn, A. and Gormley, P. and Becker, F. and Weber, Y.G. and Cilio, M.R. and Kunz, W.S. and Krause, R. and Zimprich, F. and Lemke, J.R. and Nürnberg, P. and Sander, T. and Lerche, H. and Neubauer, B.A.
Abstract:OBJECTIVE: The SCN1A gene, coding for the voltage-gated Na(+) channel alpha subunit Na(V)1.1, 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.
Keywords:Amino Acid Substitution, Case-Control Studies, Epilepsy, Missense Mutation, NAV1.1 Voltage-Gated Sodium Channel, Risk Factors, Syndrome
Source:PLoS ONE
Publisher:Public Library of Science
Page Range:e0150426
Date:18 March 2016
Additional Information:Janine Altmüller is a member of the EuroEPINOMICS CoGIE Consortium.
Official Publication:https://doi.org/10.1371/journal.pone.0150426
PubMed:View item in PubMed

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