Autor: |
Dennis Lal, Eva M Reinthaler, Borislav Dejanovic, Patrick May, Holger Thiele, Anna-Elina Lehesjoki, Günter Schwarz, Erik Riesch, M Arfan Ikram, Cornelia M van Duijn, Andre G Uitterlinden, Albert Hofman, Hannelore Steinböck, Ursula Gruber-Sedlmayr, Birgit Neophytou, Federico Zara, Andreas Hahn, Genetic Commission of the Italian League against Epilepsy, EuroEPINOMICS CoGIE Consortium, Padhraig Gormley, Felicitas Becker, Yvonne G Weber, Maria Roberta Cilio, Wolfram S Kunz, Roland Krause, Fritz Zimprich, Johannes R Lemke, Peter Nürnberg, Thomas Sander, Holger Lerche, Bernd A Neubauer |
Jazyk: |
angličtina |
Rok vydání: |
2016 |
Předmět: |
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Zdroj: |
PLoS ONE, Vol 11, Iss 3, p e0150426 (2016) |
Druh dokumentu: |
article |
ISSN: |
1932-6203 |
DOI: |
10.1371/journal.pone.0150426 |
Popis: |
ObjectiveThe 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.MethodsWe 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 interpretationWe 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. |
Databáze: |
Directory of Open Access Journals |
Externí odkaz: |
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