Using genetically diverse Collaborative Cross mouse strains to model SCN1A-related Dravet Syndrome
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Dravet Syndrome (DS) is classified as a rare neurodevelopmental and epileptic encephalopathy (DEE), characterized by persistent seizures, developmental delays, speech impairments, sleep disruptions, and other comorbidities. Although DS is considered a monogenic disease, it exhibits marked phenotypic heterogeneity that is not fully explained by the causal SCN1A variant. Understanding the genetic basis influencing phenotype severity is challenging through methods like Genome-Wide Association Studies (GWAS) due to limited data on these sporadic variants. Additionally, current DS models fail to capture the full heterogeneity of DS outcomes, restricting their translatable potential. To address these limitations, our study leverages the Collaborative Cross (CC), a panel of genetically diverse recombinant inbred mouse strains. We developed new models of DS by crossing Scn1a+/- 129SvJ male mice with five CC strains and the reference C57BL/6J (B6J). Survival and susceptibility to heat-induced seizures were assessed in a total of 257 F1 mice. Introducing genetic diversity revealed a phenotypic spectrum extending beyond the phenotypes characterized previously. Multivariate analysis provided novel insights into biological and environmental interactions influencing the phenotypic response. Overall, our work provides new insights into the factors influencing the phenotypic manifestations of DS and reinforces the importance of genetic diversity in studying complex traits.
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M.S.