{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T19:57:44Z","timestamp":1789070264526,"version":"build-2803163510"},"reference-count":32,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T00:00:00Z","timestamp":1770249600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T00:00:00Z","timestamp":1770249600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100025520","name":"Medical Research Future Fund","doi-asserted-by":"publisher","award":["GHFMCDI000002"],"award-info":[{"award-number":["GHFMCDI000002"]}],"id":[{"id":"10.13039\/501100025520","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100022878","name":"Praxis Precision Medicines","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100022878","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2026,5]]},"abstract":"Abstract<\/jats:title>\n \n Objective<\/jats:title>\n \n SCN2A<\/jats:italic>\n loss\u2010of\u2010function (LoF) variants are associated with epilepsy (onset age\u2009\u2265\u20093\u2009months), intellectual disability (ID), and autism spectrum disorder (ASD). Despite numerous identified variants and the description of phenotypic subgroups, relationships between Na\n v<\/jats:sub>\n 1.2 channel dysfunction and clinical phenotypes remain unclear. This study examined how distinct LoF mechanisms relate to phenotypic outcomes.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n Whole\u2010cell patch\u2010clamp electrophysiology was used to characterize 15 presumed LoF\n SCN2A<\/jats:italic>\n variants. Mechanism\u2013phenotype correlations were assessed in 33 patients with these variants (six recurrent) and 41 patients with 15 previously characterized LoF variants (four recurrent). Phenotypic subgroups were categorized as later onset epilepsy\u2013midinfancy (onset between 3 and 18\u2009months), later onset epilepsy\u2013childhood (onset after 18\u2009months), ID\/ASD without epilepsy, and \u201cother\u201d for unclassified cases.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Of the 15 electrophysiologically characterized\n SCN2A<\/jats:italic>\n variants, 11 caused total Na\n v<\/jats:sub>\n 1.2 LoF, three caused partial LoF, and one showed mixed LoF and gain\u2010of\u2010function (GoF) effects. Among previously published variants, seven showed total LoF, five partial LoF, and two mixed LoF\/GoF, and one was undetermined. Across both cohorts, seven of 10 recurrent variants (70%) were associated with multiple phenotypic subgroups. Partial or total Na\n v<\/jats:sub>\n 1.2 LoF variants were identified in all subgroups. Notably, a midinfancy epilepsy phenotype was observed in 22 of 24 individuals (92%) carrying a mixed LoF variant, with phenotype data unavailable for seven additional individuals. A novel LoF\u2010associated phenotype\u2014episodic ataxia with or without developmental delay or ID\u2014was identified in five of six individuals with the L1650P variant. Although episodic ataxia has been previously associated with GoF variants in\n SCN2A<\/jats:italic>\n , this is the first reported instance in individuals with a confirmed LoF variant.\n <\/jats:p>\n <\/jats:sec>\n \n Significance<\/jats:title>\n \n Distinct\n SCN2A<\/jats:italic>\n LoF phenotypes cannot be reliably linked to specific biophysical mechanisms, as both total and partial Na\n v<\/jats:sub>\n 1.2 LoF occurs across diverse phenotypes. For efficient personalized treatment, it is crucial not to rely solely on clinical phenotype to predict the underlying LoF mechanism.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/epi.70100","type":"journal-article","created":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T15:19:52Z","timestamp":1770304792000},"page":"2628-2653","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Mechanisms of\n \n SCN2A<\/i>\n <\/scp>\n loss of function do not predict presence or phenotype of epilepsy"],"prefix":"10.1002","volume":"67","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0648-0813","authenticated-orcid":false,"given":"Marsha","family":"Tan","sequence":"first","affiliation":[{"name":"Ion Channels and Human Disease Group, Florey Institute of Neuroscience and Mental Health University of Melbourne Parkville Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3210-0447","authenticated-orcid":false,"given":"Beatrice Southby","family":"Goad","sequence":"additional","affiliation":[{"name":"Murdoch Children's Research Institute Parkville Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-4917-9395","authenticated-orcid":false,"given":"Meagan","family":"Allen","sequence":"additional","affiliation":[{"name":"Murdoch Children's Research Institute Parkville Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4486-8111","authenticated-orcid":false,"given":"Jill","family":"Rodda","sequence":"additional","affiliation":[{"name":"Murdoch Children's Research Institute Parkville Victoria Australia"},{"name":"Department of Physiotherapy University of Melbourne Parkville Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5707-9448","authenticated-orcid":false,"given":"Kay L.","family":"Richards","sequence":"additional","affiliation":[{"name":"Ion Channels and Human Disease Group, Florey Institute of Neuroscience and Mental Health University of Melbourne Parkville Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9031-7348","authenticated-orcid":false,"given":"Simone L.","family":"Ardern\u2010Holmes","sequence":"additional","affiliation":[{"name":"T. Y. Nelson Department of Neurology and Neurosurgery Children's Hospital at Westmead Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9868-0184","authenticated-orcid":false,"given":"Daniel","family":"Bamborschke","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology, Children's Hospital University Hospital Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-1678-0441","authenticated-orcid":false,"given":"Daniel","family":"Fritzen","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology, Children's Hospital University Hospital Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3585-3567","authenticated-orcid":false,"given":"Inna","family":"Hughes","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Rochester Medical Center Rochester New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1122-3555","authenticated-orcid":false,"given":"Kate","family":"Riney","sequence":"additional","affiliation":[{"name":"Neurosciences Unit Queensland Children's Hospital South Brisbane Queensland Australia"},{"name":"School of Medicine University of Queensland Brisbane Queensland Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8295-1982","authenticated-orcid":false,"given":"Ana Roche","family":"Martinez","sequence":"additional","affiliation":[{"name":"Parc Taul\u00ed Hospital Universitari Institut d'Investigaci\u00f3 i Innovaci\u00f3 Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0322-2640","authenticated-orcid":false,"given":"Angelo","family":"Russo","sequence":"additional","affiliation":[{"name":"Istituto di Ricovero e Cura a 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Disorders Unit Bambino Ges\u00f9 Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, full member of European Reference Network EpiCARE Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8526-1511","authenticated-orcid":false,"given":"Angela","family":"De Dominicis","sequence":"additional","affiliation":[{"name":"Neurology, Epilepsy, and Movement Disorders Unit Bambino Ges\u00f9 Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, full member of European Reference Network EpiCARE Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8120-0287","authenticated-orcid":false,"given":"Nicola","family":"Specchio","sequence":"additional","affiliation":[{"name":"Neurology, Epilepsy, and Movement Disorders Unit Bambino Ges\u00f9 Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, full member of European Reference Network EpiCARE Rome 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":"Department of Epilepsy Genetics and Personalized Medicine Danish Epilepsy Center, member of European Reference Network EpiCARE 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\/0000-0002-2311-2174","authenticated-orcid":false,"given":"Ingrid E.","family":"Scheffer","sequence":"additional","affiliation":[{"name":"Murdoch Children's Research Institute Parkville Victoria Australia"},{"name":"Department of Neurology Royal Children's Hospital Melbourne Victoria Australia"},{"name":"Department of Paediatrics University of Melbourne Melbourne Victoria Australia"},{"name":"Florey 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