Lal, Dennis, Reinthaler, Eva M., Dejanovici, Borislav, May, Patrick ORCID: 0000-0001-8698-3770, 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 ORCID: 0000-0001-9744-5222, Hahn, Andreas, Gormley, Padhraig ORCID: 0000-0002-8908-6968, Becker, Felicitas, Weber, Yvonne G., Cilio, Maria Roberta, Kunz, Wolfram S. ORCID: 0000-0003-1113-3493, Krause, Roland ORCID: 0000-0001-9938-7126, Zimprich, Fritz ORCID: 0000-0002-6998-5480, Lemke, Johannes R., Nuernberg, Peter, Sander, Thomas, Lerche, Holger and Neubauer, Bernd A. (2016). Evaluation of Presumably Disease Causing SCN1A Variants in a Cohort of Common Epilepsy Syndromes. PLoS One, 11 (3). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1932-6203

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Lal, DennisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reinthaler, Eva M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dejanovici, BorislavUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
May, PatrickUNSPECIFIEDorcid.org/0000-0001-8698-3770UNSPECIFIED
Thiele, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lehesjoki, Anna-ElinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schwarz, GunterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Riesch, ErikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ikram, M. ArfanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Duijn, Cornelia M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Uitterlinden, Andre G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hofman, AlbertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Steinboeck, HanneloreUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gruber-Sedlmayr, UrsulaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Neophytou, BirgitUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zara, FedericoUNSPECIFIEDorcid.org/0000-0001-9744-5222UNSPECIFIED
Hahn, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gormley, PadhraigUNSPECIFIEDorcid.org/0000-0002-8908-6968UNSPECIFIED
Becker, FelicitasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weber, Yvonne G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cilio, Maria RobertaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kunz, Wolfram S.UNSPECIFIEDorcid.org/0000-0003-1113-3493UNSPECIFIED
Krause, RolandUNSPECIFIEDorcid.org/0000-0001-9938-7126UNSPECIFIED
Zimprich, FritzUNSPECIFIEDorcid.org/0000-0002-6998-5480UNSPECIFIED
Lemke, Johannes R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sander, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lerche, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Neubauer, Bernd A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-281205
DOI: 10.1371/journal.pone.0150426
Journal or Publication Title: PLoS One
Volume: 11
Number: 3
Date: 2016
Publisher: PUBLIC LIBRARY SCIENCE
Place of Publication: SAN FRANCISCO
ISSN: 1932-6203
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
NEURONAL SODIUM-CHANNEL; SEVERE MYOCLONIC EPILEPSY; FEBRILE SEIZURES PLUS; GENERALIZED EPILEPSY; DRAVET SYNDROME; ITALIAN PATIENTS; MUTATION; PREVALENCE; PHENOTYPE; GENOTYPEMultiple languages
Multidisciplinary SciencesMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/28120

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