Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With Epilepsy With <i>KCNC2</i> Pathogenic Variants.

Abstract

<i>KCNC2</i> encodes Kv3.2, a member of the Shaw-related (Kv3) voltage-gated potassium channel subfamily, which is important for sustained high-frequency firing and optimized energy efficiency of action potentials in the brain. The objective of this study was to analyze the clinical phenotype, genetic background, and biophysical function of disease-associated Kv3.2 variants. Individuals with <i>KCNC2</i> variants detected by exome sequencing were selected for clinical, further genetic, and functional analysis. Cases were referred through clinical and research collaborations. Selected de novo variants were examined electrophysiologically in <i>Xenopus laevis</i> oocytes. We identified novel <i>KCNC2</i> variants in 18 patients with various forms of epilepsy, including genetic generalized epilepsy (GGE), developmental and epileptic encephalopathy (DEE) including early-onset absence epilepsy, focal epilepsy, and myoclonic-atonic epilepsy. Of the 18 variants, 10 were de novo and 8 were classified as modifying variants. Eight drug-responsive patients became seizure-free using valproic acid as monotherapy or in combination, including severe DEE cases. Functional analysis of 4 variants demonstrated gain of function in 3 severely affected DEE cases and loss of function in 1 case with a milder phenotype (GGE) as the underlying pathomechanisms. These findings implicate <i>KCNC2</i> as a novel causative gene for epilepsy and emphasize the critical role of K_V3.2 in the regulation of brain excitability.