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DEEs are primarily attributed to genetic causes and an increasing number of cases have been correlated with variants in ion channel genes. In this study, we report a child with an early severe DEE. Whole exome sequencing showed a de novo heterozygous variant (c.4873\u20134881 duplication) in the <jats:italic>SCN8A<\/jats:italic> gene and an inherited heterozygous variant (c.952G\u2009&gt;\u2009A) in the <jats:italic>CACNA1H<\/jats:italic> gene encoding for Na<jats:sub>v<\/jats:sub>1.6 voltage-gated sodium and Ca<jats:sub>v<\/jats:sub>3.2 voltage-gated calcium channels, respectively. In vitro functional analysis of human Na<jats:sub>v<\/jats:sub>1.6 and Ca<jats:sub>v<\/jats:sub>3.2 channel variants revealed mild but significant alterations of their gating properties that were in general consistent with a gain- and loss-of-channel function, respectively. Although additional studies will be required to confirm the actual pathogenic involvement of <jats:italic>SCN8A<\/jats:italic> and <jats:italic>CACNA1H<\/jats:italic>, these findings add to the notion that rare ion channel variants may contribute to the etiology of DEEs.<\/jats:p>","DOI":"10.1186\/s13041-021-00838-y","type":"journal-article","created":{"date-parts":[[2021,8,16]],"date-time":"2021-08-16T09:04:23Z","timestamp":1629104663000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["De novo SCN8A and inherited rare CACNA1H variants associated with severe developmental and epileptic encephalopathy"],"prefix":"10.1186","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0887-7670","authenticated-orcid":false,"given":"Robin N.","family":"Stringer","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7931-922X","authenticated-orcid":false,"given":"Bohumila","family":"Jurkovicova-Tarabova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ivana A.","family":"Souza","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Judy","family":"Ibrahim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomas","family":"Vacik","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Waseem Mahmoud","family":"Fathalla","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jozef","family":"Hertecant","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0644-9066","authenticated-orcid":false,"given":"Gerald W.","family":"Zamponi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9207-0978","authenticated-orcid":false,"given":"Lubica","family":"Lacinova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0040-1109","authenticated-orcid":false,"given":"Norbert","family":"Weiss","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,8,16]]},"reference":[{"issue":"1","key":"838_CR1","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1684\/epd.2021.1244","volume":"23","author":"S Raga","year":"2021","unstructured":"Raga S, Specchio N, Rheims S, Wilmshurst JM. 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