Aberrant RNA splicing caused by variant in DEPDC5 identified in a patient with pharmacoresistant epilepsy.

Familial focal epilepsy with variable foci-1 (FFEVF1) is an autosomal dominant form of epilepsy. The phenotypic spectrum of FFEVF1 is wide, with incomplete penetrance. Therefore, making a definite diagnosis based solely on the phenotype of patients is challenging. We report a 6-year-old female patient presenting with epilepsy, global developmental delay, coarctation of the aortic arch, and neuronal migration disorder. Trio whole-exome sequencing as well as Sanger sequencing were conducted to identify familial epilepsy-associated variants in the family. The pathogenicity of the variant was confirmed through mRNA splicing analysis in vivo and in vitro. Genetic testing identified a heterozygous variant, c.2633 + 2T > C, in the DEPDC5 gene. The pathogenicity of this variant was substantiated through in vivo and in vitro mRNA splicing analyses. These studies demonstrated that the variant induces multiple aberrant splicing events, all resulting in reading frame alterations. Consequently, the variant was classified as Likely Pathogenic according to ACMG guidelines. This study establishes a genetic diagnosis for the patient’s pharmacoresistant epilepsy, facilitating precise genetic counseling. Furthermore, a definitive diagnosis aids in reproductive risk assessment and supports future pre-implantation or prenatal testing for the family. Finally, this novel c.2633 + 2T > C variant expands the known mutational spectrum of DEPDC5.