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However, emerging evidence suggests separate entities of <jats:italic>SCN1A<\/jats:italic>\u2010related disorders due to gain\u2010of\u2010function variants. Here, we aim to refine the clinical, genetic, and functional electrophysiological features of a recurrent p.R1636Q gain\u2010of\u2010function variant, identified in four individuals at a single center.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Individuals carrying the recurrent <jats:italic>SCN1A<\/jats:italic> p.R1636Q variant were identified through diagnostic testing. Whole cell voltage\u2010clamp electrophysiological recording in HEK\u2010293\u2009T cells was performed to compare the properties of sodium channels containing wild\u2010type Na<jats:sub>v<\/jats:sub>1.1 or Na<jats:sub>v<\/jats:sub>1.1\u2010R1636Q along with both Na<jats:sub>v<\/jats:sub>\u03b21 and Na<jats:sub>v<\/jats:sub>\u03b22 subunits, including response to oxcarbazepine. To delineate differences from other <jats:italic>SCN1A<\/jats:italic>\u2010related epilepsies, we analyzed electronic medical records.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>All four individuals had an early onset DEE characterized by focal tonic seizures and additional seizure types starting in the first few weeks of life. Electrophysiological analysis showed a mixed gain\u2010of\u2010function effect with normal current density, a leftward (hyperpolarized) shift of steady\u2010state inactivation, and slower inactivation kinetics leading to a prominent late sodium current. The observed functional changes closely paralleled effects of pathogenic variants in <jats:italic>SCN3A<\/jats:italic> and <jats:italic>SCN8A<\/jats:italic> at corresponding positions. Both wild type and variant exhibited sensitivity to block by oxcarbazepine, partially correcting electrophysiological abnormalities of the <jats:italic>SCN1A<\/jats:italic> p.R1636Q variant. Clinically, a single individual responded to treatment with oxcarbazepine. Across 51 individuals with <jats:italic>SCN1A<\/jats:italic>\u2010related epilepsies, those with the recurrent p.R1636Q variants had the earliest ages at onset.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>The recurrent <jats:italic>SCN1A<\/jats:italic> p.R1636Q variant causes a clinical entity with a wider clinical spectrum than previously reported, characterized by neonatal onset epilepsy and absence of prominent movement disorder. Functional consequences of this variant lead to mixed loss and gain of function that is partially corrected by oxcarbazepine. The recurrent p.R1636Q variant represents one of the most common causes of early onset <jats:italic>SCN1A<\/jats:italic>\u2010related epilepsies with separate treatment and prognosis implications.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.17444","type":"journal-article","created":{"date-parts":[[2022,10,26]],"date-time":"2022-10-26T14:20:53Z","timestamp":1666794053000},"page":"1318-1330","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["<scp><i>SCN1A<\/i><\/scp> gain\u2010of\u2010function mutation causing an early onset epileptic encephalopathy"],"prefix":"10.1111","volume":"64","author":[{"given":"J\u00e9r\u00f4me","family":"Clatot","sequence":"first","affiliation":[{"name":"Division of Neurology, Department of Pediatrics Children's Hospital of Philadelphia  Philadelphia Pennsylvania USA"},{"name":"Epilepsy NeuroGenetics Initiative Children's Hospital of Philadelphia  Philadelphia Pennsylvania 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