Variants in ATP6V0C are associated with Dravet-like developmental and epileptic encephalopathy.

Objective: Dravet syndrome (DS) is a developmental and epileptic encephalopathy. Diagnosis is clinical, but ~90% of patients have pathogenic variants in SCN1A. ATP6V0C has recently been proposed as a novel candidate gene for epilepsy, with or without developmental delay. Here we describe two adult patients with a clinical diagnosis of DS associated with ATP6V0C variants.

Methods: Patients with developmental and epileptic encephalopathies were evaluated by physicians who are experts in DS, and their clinical diagnosis was correlated with genetic findings. A subgroup of those patients with DS but without known genetic causes were evaluated through gene panels, whole exome sequencing, and chromosome microarray. Phenotype was determined by pediatric and adult chart reviews, interviews, and physical examinations.

Results: Of 753 patients with DS, two unrelated individuals with classic features of DS during childhood and adulthood were identified with heterozygous de novo missense variants in ATP6V0C (c.319G > C, p.(Gly107Arg) and c.284C > T, p.(Ala95Val), respectively). Both variants were absent in normal populations and computational prediction algorithms suggested deleterious effects on protein structure and/or function. No disease-causing variants in other genes previously associated with DS were found.

Significance: Here we describe two adult patients with Dravet-like syndrome and pathogenic/likely pathogenic variants in ATP6V0C. We propose that abnormal ATP6V0C function can, at the severe end of the clinical spectrum, be associated with Dravet-like phenotype. This is relevant, as these patients would not qualify for disease-modifying antisense nucleotide or gene therapies targeting SCN1A.