Pathogenic in-Frame Variants in SCN8A: Expanding the Genetic Landscape of SCN8A-Associated Disease

• DOI: 10.3389/fphar.2021.748415
• Publication Date: 2021-11-17T07:25:57Z
• Authors: Jennifer C. Wong; Kameryn M. Butler; Lindsey Shapiro; Jacquelyn T. Thelin; Kari A. Mattison; Kathryn B. Garber; Paula C. Goldenberg; Shobana Kubendran; G. Bradley Schaefer; Andrew Escayg
• Keywords: Clinical phenotype

Numerous SCN8A mutations have been identified, of which, the majority are de novo missense variants. Most result in epileptic encephalopathy; however, some associated with less severe phenotypes. Mouse models generated by knock-in human exhibit seizures and a range behavioral abnormalities. To date, there only few Scn8a mouse in-frame deletions or insertions, notably, none these lines increased seizure susceptibility. In current study, we report generation characterization two (ΔIRL/+ ΔVIR/+) carrying overlapping within voltage sensor domain 4 (DIVS4). Both show susceptibility infrequent spontaneous seizures. We also describe unrelated patients same deletion DIV S5-S6 pore region, highlighting clinical relevance this class mutations.