{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T02:32:28Z","timestamp":1790994748372,"version":"4.1.0"},"reference-count":41,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2024,2,27]],"date-time":"2024-02-27T00:00:00Z","timestamp":1708992000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100012012","name":"Dravet Syndrome UK","doi-asserted-by":"publisher","award":["16GLW00"],"award-info":[{"award-number":["16GLW00"]}],"id":[{"id":"10.13039\/100012012","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2024,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p><jats:italic>SCN1A<\/jats:italic> variants are associated with epilepsy syndromes ranging from mild genetic epilepsy with febrile seizures plus (GEFS+) to severe Dravet syndrome (DS). Many variants are de novo, making early phenotype prediction difficult, and genotype\u2013phenotype associations remain poorly understood.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We assessed data from a retrospective cohort of 1018 individuals with <jats:italic>SCN1A\u2010<\/jats:italic>related epilepsies. We explored relationships between variant characteristics (position, in silico prediction scores: Combined Annotation Dependent Depletion (CADD), Rare Exome Variant Ensemble Learner (REVEL), <jats:italic>SCN1A<\/jats:italic> genetic score), seizure characteristics, and epilepsy phenotype.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>DS had earlier seizure onset than other GEFS+ phenotypes (5.3 vs. 12.0\u2009months, <jats:italic>p<\/jats:italic>\u2009&lt;\u2009.001). In silico variant scores were higher in DS versus GEFS+ (<jats:italic>p<\/jats:italic>\u2009&lt;\u2009.001). Patients with missense variants in functionally important regions (conserved N\u2010terminus, S4\u2013S6) exhibited earlier seizure onset (6.0 vs. 7.0\u2009months, <jats:italic>p<\/jats:italic>\u2009=\u2009.003) and were more likely to have DS (280\/340); those with missense variants in nonconserved regions had later onset (10.0 vs. 7.0\u2009months, <jats:italic>p<\/jats:italic>\u2009=\u2009.036) and were more likely to have GEFS+ (15\/29, \u03c7<jats:sup>2<\/jats:sup>\u2009=\u200919.16, <jats:italic>p<\/jats:italic>\u2009&lt;\u2009.001). A minority of protein\u2010truncating variants were associated with GEFS+ (10\/393) and more likely to be located in the proximal first and last exon coding regions than elsewhere in the gene (9.7% vs. 1.0%, <jats:italic>p<\/jats:italic>\u2009&lt;\u2009.001). Carriers of the same missense variant exhibited less variability in age at seizure onset compared with carriers of different missense variants for both DS (1.9 vs. 2.9\u2009months, <jats:italic>p<\/jats:italic>\u2009=\u2009.001) and GEFS+ (8.0 vs. 11.0\u2009months, <jats:italic>p<\/jats:italic>\u2009=\u2009.043). Status epilepticus as presenting seizure type is a highly specific (95.2%) but nonsensitive (32.7%) feature of DS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>Understanding genotype\u2013phenotype associations in <jats:italic>SCN1A<\/jats:italic>\u2010related epilepsies is critical for early diagnosis and management. We demonstrate an earlier disease onset in patients with missense variants in important functional regions, the occurrence of GEFS+ truncating variants, and the value of in silico prediction scores. Status epilepticus as initial seizure type is a highly specific, but not sensitive, early feature of DS.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.17882","type":"journal-article","created":{"date-parts":[[2024,2,27]],"date-time":"2024-02-27T09:20:10Z","timestamp":1709025610000},"page":"1046-1059","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Genotype\u2013phenotype associations in 1018 individuals with <i>SCN1A<\/i>\u2010related epilepsies"],"prefix":"10.1111","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7983-3782","authenticated-orcid":false,"given":"Declan","family":"Gallagher","sequence":"first","affiliation":[{"name":"School of Health and Wellbeing University of Glasgow  Glasgow UK"},{"name":"Paediatric Neurosciences Research Group Royal Hospital for Children  Glasgow UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo","family":"P\u00e9rez\u2010Palma","sequence":"additional","affiliation":[{"name":"Universidad del Desarrollo, Centro de Gen\u00e9tica y Gen\u00f3mica, Facultad de Medicina Cl\u00ednica Alemana  Santiago Chile"},{"name":"Cologne Center for Genomics University of Cologne  Cologne Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Bruenger","sequence":"additional","affiliation":[{"name":"Cologne Center for Genomics University of Cologne  Cologne Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ismael","family":"Ghanty","sequence":"additional","affiliation":[{"name":"School of Health and Wellbeing University of Glasgow  Glasgow UK"},{"name":"Paediatric Neurosciences Research Group Royal Hospital for Children  Glasgow UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Brilstra","sequence":"additional","affiliation":[{"name":"Department of Genetics University Medical Center  Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Berten","family":"Ceulemans","sequence":"additional","affiliation":[{"name":"Department of Child Neurology University Hospital Antwerp  Antwerp Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Chemaly","sequence":"additional","affiliation":[{"name":"Reference Center for Rare Epilepsies, Department of Pediatric Neurology H\u00f4pital Necker\u2010Enfants Malades, Universit\u00e9 de Paris  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2107-9224","authenticated-orcid":false,"given":"Iris","family":"de Lange","sequence":"additional","affiliation":[{"name":"Department of Genetics University Medical Center  Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7212-9554","authenticated-orcid":false,"given":"Christel","family":"Depienne","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University Hospital Essen University of Duisburg\u2010Essen  Essen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renzo","family":"Guerrini","sequence":"additional","affiliation":[{"name":"Neuroscience Department Children's Hospital A. Meyer Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) and University of Florence  Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6790-6251","authenticated-orcid":false,"given":"Davide","family":"Mei","sequence":"additional","affiliation":[{"name":"Neuroscience Department Children's Hospital A. Meyer Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) and University of Florence  Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9664-1448","authenticated-orcid":false,"given":"Rikke S.","family":"M\u00f8ller","sequence":"additional","affiliation":[{"name":"Danish Epilepsy Center, Filadelfia  Dianalund Denmark"},{"name":"Department of Regional Health Research, Faculty of Health Sciences University of Southern Denmark  Odense Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5877-4074","authenticated-orcid":false,"given":"Rima","family":"Nabbout","sequence":"additional","affiliation":[{"name":"Reference Center for Rare Epilepsies, Department of Pediatric Neurology H\u00f4pital Necker\u2010Enfants Malades, Universit\u00e9 de Paris  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brigid M.","family":"Regan","sequence":"additional","affiliation":[{"name":"Department of Medicine, Epilepsy Research Centre University of Melbourne, Austin Health  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5260-7187","authenticated-orcid":false,"given":"Amy L.","family":"Schneider","sequence":"additional","affiliation":[{"name":"Department of Medicine, Epilepsy Research Centre University of Melbourne, Austin Health  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2311-2174","authenticated-orcid":false,"given":"Ingrid E.","family":"Scheffer","sequence":"additional","affiliation":[{"name":"Department of Medicine, Epilepsy Research Centre University of Melbourne, Austin Health  Melbourne Victoria Australia"},{"name":"University of Melbourne, Royal Children's Hospital, Florey and Murdoch Children's Research Institutes  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7545-518X","authenticated-orcid":false,"given":"An\u2010Sofie","family":"Schoonjans","sequence":"additional","affiliation":[{"name":"Department of Child Neurology University Hospital Antwerp  Antwerp Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph D.","family":"Symonds","sequence":"additional","affiliation":[{"name":"School of Health and Wellbeing University of Glasgow  Glasgow UK"},{"name":"Paediatric Neurosciences Research Group Royal Hospital for Children  Glasgow UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Weckhuysen","sequence":"additional","affiliation":[{"name":"Applied &amp; Translational Neurogenomics Group, VIB Center for Molecular Neurology  Antwerp Belgium"},{"name":"Neurology Department University Hospital Antwerp  Antwerp Belgium"},{"name":"Translational Neurosciences University of Antwerp  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