Please use this identifier to cite or link to this item: https://doi.org/10.1371/journal.pone.0150426
Title: Evaluation of presumably disease causing SCN1A variants in a cohort of common epilepsy syndromes
Authors: Lal D.
Reinthaler E.M.
Dejanovic B.
May P.
Thiele H.
Lehesjoki A.-E.
Schwarz G.
Riesch E.
Ikram M.A. 
Van Duijn C.M.
Uitterlinden A.G.
Hofman A.
Steinböck 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.
Nürnberg P.
Sander T.
Lerche H.
Neubauer B.A.
Palotie A.
Ruppert A.-K.
Suls A.
Siren A.
Koeleman B.
Haberlandt E.
Ronen G.M.
Caglayan H.
Hjalgrim H.
Muhle H.
Schulz H.
Helbig I.
Altmüller J.
Geldner J.
Schubert J.
Jabbari K.
Everett K.
Feucht M.
Balestri M.
Nothnagel M.
Striano P.
Møller R.S.
Nabbout R.
Balling R.
Baulac S.
Bianchi A.
La Neve A.
Minetti C.
Giuseppe C.
Keywords: sodium channel Nav1.1
SCN1A protein, human
sodium channel Nav1.1
Article
cohort analysis
controlled study
disease classification
epilepsy
exome
female
follow up
gene frequency
gene mutation
gene sequence
genetic counseling
genetic risk
genetic screening
genetic variability
human
major clinical study
male
missense mutation
pathogenicity
penetrance
SCN1A gene
amino acid substitution
case control study
clinical trial
epilepsy
genetics
missense mutation
multicenter study
risk factor
syndrome
Amino Acid Substitution
Case-Control Studies
Epilepsy
Female
Humans
Male
Mutation, Missense
NAV1.1 Voltage-Gated Sodium Channel
Risk Factors
Syndrome
Issue Date: 2016
Citation: Lal D., Reinthaler E.M., Dejanovic B., May P., Thiele H., Lehesjoki A.-E., Schwarz G., Riesch E., Ikram M.A., Van Duijn C.M., Uitterlinden A.G., Hofman A., Steinböck 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., Nürnberg P., Sander T., Lerche H., Neubauer B.A., Palotie A., Ruppert A.-K., Suls A., Siren A., Koeleman B., Haberlandt E., Ronen G.M., Caglayan H., Hjalgrim H., Muhle H., Schulz H., Helbig I., Altmüller J., Geldner J., Schubert J., Jabbari K., Everett K., Feucht M., Balestri M., Nothnagel M., Striano P., Møller R.S., Nabbout R., Balling R., Baulac S., Bianchi A., La Neve A., Minetti C., Giuseppe C. (2016). Evaluation of presumably disease causing SCN1A variants in a cohort of common epilepsy syndromes. PLoS ONE 11 (3) : e0150426. ScholarBank@NUS Repository. https://doi.org/10.1371/journal.pone.0150426
Rights: CC0 1.0 Universal
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 × 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.
Source Title: PLoS ONE
URI: https://scholarbank.nus.edu.sg/handle/10635/161583
ISSN: 19326203
DOI: 10.1371/journal.pone.0150426
Rights: CC0 1.0 Universal
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