{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T14:52:55Z","timestamp":1791903175999,"version":"4.3.4"},"reference-count":62,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2020,2,23]],"date-time":"2020-02-23T00:00:00Z","timestamp":1582416000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2020,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Voltage\u2010gated sodium channels (SCNs) share similar amino acid sequence, structure, and function. Genetic variants in the four human brain\u2010expressed <jats:italic>SCN<\/jats:italic> genes <jats:italic>SCN1A\/2A\/3A\/8A<\/jats:italic> have been associated with heterogeneous epilepsy phenotypes and neurodevelopmental disorders. To better understand the biology of seizure susceptibility in <jats:italic>SCN<\/jats:italic>\u2010related epilepsies, our aim was to determine similarities and differences between sodium channel disorders, allowing us to develop a broader perspective on precision treatment than on an individual gene level alone.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We analyzed genotype\u2010phenotype correlations in large <jats:italic>SCN<\/jats:italic>\u2010patient cohorts and applied variant constraint analysis to identify severe sodium channel disease. We examined temporal patterns of human <jats:italic>SCN<\/jats:italic> expression and correlated functional data from in vitro studies with clinical phenotypes across different sodium channel disorders.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Comparing 865 epilepsy patients (504 <jats:italic>SCN1A<\/jats:italic>, 140 <jats:italic>SCN2A<\/jats:italic>, 171 <jats:italic>SCN8A<\/jats:italic>, four <jats:italic>SCN3A<\/jats:italic>, 46 copy number variation [CNV] cases) and analysis of 114 functional studies allowed us to identify common patterns of presentation. All four epilepsy\u2010associated <jats:italic>SCN<\/jats:italic> genes demonstrated significant constraint in both protein truncating and missense variation when compared to other <jats:italic>SCN<\/jats:italic> genes. We observed that age at seizure onset is related to <jats:italic>SCN<\/jats:italic> gene expression over time. Individuals with gain\u2010of\u2010function <jats:italic>SCN2A\/3A\/8A<\/jats:italic> missense variants or CNV duplications share similar characteristics, most frequently present with early onset epilepsy (&lt;3\u00a0months), and demonstrate good response to sodium channel blockers (SCBs). Direct comparison of corresponding <jats:italic>SCN<\/jats:italic> variants across different <jats:italic>SCN<\/jats:italic> subtypes illustrates that the functional effects of variants in corresponding channel locations are similar; however, their clinical manifestation differs, depending on their role in different types of neurons in which they are expressed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>Variant function and location within one channel can serve as a surrogate for variant effects across related sodium channels. Taking a broader view on precision treatment suggests that in those patients with a suspected underlying genetic epilepsy presenting with neonatal or early onset seizures (&lt;3\u00a0months), SCBs should be considered.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.16438","type":"journal-article","created":{"date-parts":[[2020,2,24]],"date-time":"2020-02-24T05:23:55Z","timestamp":1582521835000},"page":"387-399","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":98,"title":["Biological concepts in human sodium channel epilepsies and their relevance in clinical practice"],"prefix":"10.1111","volume":"61","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7728-6903","authenticated-orcid":false,"given":"Andreas","family":"Brunklaus","sequence":"first","affiliation":[{"name":"Paediatric Neurosciences Research Group Royal Hospital for Children Glasgow UK"},{"name":"School of Medicine University of Glasgow Glasgow 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