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Individuals with Dravet syndrome have developmental delays, elevated risk for sudden unexpected death in epilepsy (SUDEP), and have multiple seizure types that are often refractory to treatment. Although most Dravet syndrome variants arise de novo, there are cases where an <jats:italic>SCN1A<\/jats:italic> variant was inherited from mildly affected parents, as well as some individuals with de novo loss-of-function or truncation mutations that presented with milder phenotypes. This suggests that disease severity is influenced by other factors that modify expressivity of the primary mutation, which likely includes genetic modifiers. Consistent with this, the <jats:italic>Scn1a<\/jats:italic><jats:sup>+\/\u2212<\/jats:sup> mouse model of Dravet syndrome exhibits strain-dependent variable phenotype severity. <jats:italic>Scn1a<\/jats:italic><jats:sup>+\/\u2212<\/jats:sup> mice on the 129S6\/SvEvTac (129) strain have no overt phenotype and a normal lifespan, while [C57BL\/6Jx129]F1.<jats:italic>Scn1a<\/jats:italic><jats:sup>+\/\u2212<\/jats:sup> mice have severe epilepsy with high rates of premature death. Low resolution genetic mapping identified several Dravet syndrome modifier (<jats:italic>Dsm<\/jats:italic>) loci responsible for the strain-dependent difference in survival of <jats:italic>Scn1a<\/jats:italic><jats:sup>+\/\u2212<\/jats:sup> mice. To confirm the <jats:italic>Dsm5<\/jats:italic> locus and refine its position, we generated interval-specific congenic strains carrying 129-derived chromosome 11 alleles on the C57BL\/6J strain and localized <jats:italic>Dsm5<\/jats:italic> to a 5.9\u00a0Mb minimal region. We then performed candidate gene analysis in the modifier region. Consideration of brain-expressed genes with expression or coding sequence differences between strains along with gene function suggested numerous strong candidates, including several protein coding genes and two miRNAs that may regulate <jats:italic>Scn1a<\/jats:italic> transcript.<\/jats:p>","DOI":"10.1007\/s00335-022-09955-y","type":"journal-article","created":{"date-parts":[[2022,5,23]],"date-time":"2022-05-23T20:33:33Z","timestamp":1653338013000},"page":"565-574","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Fine mapping and candidate gene analysis of a dravet syndrome modifier locus on mouse chromosome 11"],"prefix":"10.1007","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1726-4769","authenticated-orcid":false,"given":"Jennifer A.","family":"Kearney","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Letonia D.","family":"Copeland-Hardin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samantha","family":"Duarte","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicole A.","family":"Zachwieja","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isaiah K.","family":"Eckart-Frank","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicole A.","family":"Hawkins","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2022,5,23]]},"reference":[{"key":"9955_CR1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.05005","author":"V Agarwal","year":"2015","unstructured":"Agarwal V, Bell GW, Nam JW, Bartel DP (2015) Predicting effective microRNA target sites in mammalian mRNAs. 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JAK receives research funding from Praxis Precision Medicines and Pfizer. NAH serves as a consultant to NeuroCycle Therapeutics. All other authors have declared that no competing interests exist.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"All animal care and experimental procedures were approved by the Northwestern University Animal Care and Use Committee in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}}]}}