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

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