title: Evaluation of Presumably Disease Causing SCN1A Variants in a Cohort of Common Epilepsy Syndromes.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Cologne Center for Genomics, University of Cologne, Cologne, Germany.|Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: Dennis
authors.initials: D
authors.lastname: Lal
authors.affiliation: Department of Neurology, Medical University of Vienna, Vienna, Austria.
authors.forename: Eva M
authors.initials: EM
authors.lastname: Reinthaler
authors.affiliation: Institute of Biochemistry, Department of Chemistry, University of Cologne, Cologne, Germany.
authors.forename: Borislav
authors.initials: B
authors.lastname: Dejanovic
authors.affiliation: Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg.
authors.forename: Patrick
authors.initials: P
authors.lastname: May
authors.affiliation: Cologne Center for Genomics, University of Cologne, Cologne, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Thiele
authors.affiliation: Folkhälsan Institute of Genetics, Helsinki, Finland.|Neuroscience Center, University of Helsinki, Helsinki, Finland.|Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.
authors.forename: Anna-Elina
authors.initials: AE
authors.lastname: Lehesjoki
authors.affiliation: Institute of Biochemistry, Department of Chemistry, University of Cologne, Cologne, Germany.
authors.forename: Günter
authors.initials: G
authors.lastname: Schwarz
authors.affiliation: CeGaT GmbH-Centre for Genomics and Transcriptomics, Tübingen, Germany.
authors.forename: Erik
authors.initials: E
authors.lastname: Riesch
authors.affiliation: Departments of Epidemiology, Neurology, Radiology, Erasmus Medical Center, Rotterdam, Netherlands.
authors.forename: M Arfan
authors.initials: MA
authors.lastname: Ikram
authors.affiliation: Departments of Epidemiology, Neurology, Radiology, Erasmus Medical Center, Rotterdam, Netherlands.
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, Netherlands.
authors.forename: Andre G
authors.initials: AG
authors.lastname: Uitterlinden
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, Rotterdam, Netherlands.
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.affiliation: Private Practice for Pediatrics, Vienna, Austria.
authors.forename: Hannelore
authors.initials: H
authors.lastname: Steinböck
authors.affiliation: Department of Pediatrics, Medical University of Graz, Graz, Austria.
authors.forename: Ursula
authors.initials: U
authors.lastname: Gruber-Sedlmayr
authors.affiliation: St. Anna Children's Hospital, Department of Neuropediatrics, Vienna, Austria.
authors.forename: Birgit
authors.initials: B
authors.lastname: Neophytou
authors.affiliation: Laboratory of Neurogenetics and Neuroscience, Institute G. Gaslini, Genova, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Zara
authors.affiliation: Department of Neuropediatrics, University Medical Center Giessen and Marburg, Giessen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Hahn
authors.affiliation: Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: Padhraig
authors.initials: P
authors.lastname: Gormley
authors.affiliation: Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
authors.forename: Felicitas
authors.initials: F
authors.lastname: Becker
authors.affiliation: Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
authors.forename: Yvonne G
authors.initials: YG
authors.lastname: Weber
authors.affiliation: Departments of Neurology and Pediatrics, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Maria Roberta
authors.initials: MR
authors.lastname: Cilio
authors.affiliation: Department of Epileptology, University of Bonn, Bonn, Germany.
authors.forename: Wolfram S
authors.initials: WS
authors.lastname: Kunz
authors.affiliation: Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg.
authors.forename: Roland
authors.initials: R
authors.lastname: Krause
authors.affiliation: Department of Neurology, Medical University of Vienna, Vienna, Austria.
authors.forename: Fritz
authors.initials: F
authors.lastname: Zimprich
authors.affiliation: Institute of Human Genetics, University of Leipzig, Leipzig, Germany.
authors.forename: Johannes R
authors.initials: JR
authors.lastname: Lemke
authors.affiliation: Cologne Center for Genomics, University of Cologne, Cologne, Germany.|Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: Cologne Center for Genomics, University of Cologne, Cologne, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Sander
authors.affiliation: Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Lerche
authors.affiliation: Department of Neuropediatrics, University Medical Center Giessen and Marburg, Giessen, Germany.
authors.forename: Bernd A
authors.initials: BA
authors.lastname: Neubauer
mesh_terms: D019943:Amino Acid Substitution; D016022:Case-Control Studies; D004827:Epilepsy / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000235:genetics*; D012307:Risk Factors; D013577:Syndrome
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; C568242:SCN1A protein, human