Modifier Genes of Dravet Syndrome

Abstract

De novo mutations in the neuronal voltage-gated sodium channel gene SCN1A are associated with Dravet syndrome (severe myoclonic epilepsy of infancy). The severity of phenotype among patients varies greatly indicating the complicated action of environmental factors and genetic modifiers. Heterozygotes mice carrying Scn1a mutation display disease phenotypes recapitulate symptoms observed in Dravet patients. We have generated Scn1a point mutation knock-in (KI) mice; as we backcross into the C57BL/6 (B6) strain, the lethality phenotype is significantly higher than that in 129 strain in a quantitative fashion, indicating the existence of detrimental modifiers in the background. Our aim is to clone these modifier genes by phenotyping the F2 hybrid using the time of lethality as a quantitative trait and performing whole-genome genotyping followed by using statistical QTL mapping methods for selective genotyping strategy to identify the genetic intervals and candidate modifier genes of Dravet syndrome.?