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Evaluation of Presumably Disease Causing SCN1A Variants in a Cohort of Common Epilepsy Syndromes
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 ar...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4798642/ https://www.ncbi.nlm.nih.gov/pubmed/26990884 http://dx.doi.org/10.1371/journal.pone.0150426 |
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author | Lal, Dennis Reinthaler, Eva M. Dejanovic, Borislav May, Patrick Thiele, Holger Lehesjoki, Anna-Elina Schwarz, Günter Riesch, Erik Ikram, M. Arfan van Duijn, Cornelia M. Uitterlinden, Andre G. Hofman, Albert Steinböck, 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. Nürnberg, Peter Sander, Thomas Lerche, Holger Neubauer, Bernd A. |
author_facet | Lal, Dennis Reinthaler, Eva M. Dejanovic, Borislav May, Patrick Thiele, Holger Lehesjoki, Anna-Elina Schwarz, Günter Riesch, Erik Ikram, M. Arfan van Duijn, Cornelia M. Uitterlinden, Andre G. Hofman, Albert Steinböck, 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. Nürnberg, Peter Sander, Thomas Lerche, Holger Neubauer, Bernd A. |
author_sort | Lal, Dennis |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4798642 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-47986422016-03-23 Evaluation of Presumably Disease Causing SCN1A Variants in a Cohort of Common Epilepsy Syndromes Lal, Dennis Reinthaler, Eva M. Dejanovic, Borislav May, Patrick Thiele, Holger Lehesjoki, Anna-Elina Schwarz, Günter Riesch, Erik Ikram, M. Arfan van Duijn, Cornelia M. Uitterlinden, Andre G. Hofman, Albert Steinböck, 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. Nürnberg, Peter Sander, Thomas Lerche, Holger Neubauer, Bernd A. PLoS One Research Article 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. Public Library of Science 2016-03-18 /pmc/articles/PMC4798642/ /pubmed/26990884 http://dx.doi.org/10.1371/journal.pone.0150426 Text en https://creativecommons.org/publicdomain/zero/1.0/ This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 (https://creativecommons.org/publicdomain/zero/1.0/) public domain dedication. |
spellingShingle | Research Article Lal, Dennis Reinthaler, Eva M. Dejanovic, Borislav May, Patrick Thiele, Holger Lehesjoki, Anna-Elina Schwarz, Günter Riesch, Erik Ikram, M. Arfan van Duijn, Cornelia M. Uitterlinden, Andre G. Hofman, Albert Steinböck, 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. Nürnberg, Peter Sander, Thomas Lerche, Holger Neubauer, Bernd A. Evaluation of Presumably Disease Causing SCN1A Variants in a Cohort of Common Epilepsy Syndromes |
title | Evaluation of Presumably Disease Causing SCN1A Variants in a Cohort of Common Epilepsy Syndromes |
title_full | Evaluation of Presumably Disease Causing SCN1A Variants in a Cohort of Common Epilepsy Syndromes |
title_fullStr | Evaluation of Presumably Disease Causing SCN1A Variants in a Cohort of Common Epilepsy Syndromes |
title_full_unstemmed | Evaluation of Presumably Disease Causing SCN1A Variants in a Cohort of Common Epilepsy Syndromes |
title_short | Evaluation of Presumably Disease Causing SCN1A Variants in a Cohort of Common Epilepsy Syndromes |
title_sort | evaluation of presumably disease causing scn1a variants in a cohort of common epilepsy syndromes |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4798642/ https://www.ncbi.nlm.nih.gov/pubmed/26990884 http://dx.doi.org/10.1371/journal.pone.0150426 |
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