Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With Epilepsy With KCNC2 Pathogenic Variants

17. Mai 2022

Schwarz N1, Seiffert S1, Pendziwiat M1, Rademacher AV1, Brünger T1, Hedrich UBS1, Augustijn PB1, Baier H1, Bayat A1, Bisulli F1, Buono RJ1, Bruria BZ1, Doyle MG1, Guerrini R1, Heimer G1, Iacomino M1, Kearney H1, Klein KM1, Kousiappa I1, Kunz WS1, Lerche H1, Licchetta L1, Lohmann E1, Minardi R1, McDonald M1, Montgomery S1, Mulahasanovic L1, Oegema R1, Ortal B1, Papacostas SS1, Ragona F1, Granata T1, Reif PS1, Rosenow F1, Rothschild A1, Scudieri P1, Striano P1, Tinuper P1, Tanteles GA1, Vetro A1, Zahnert F1, Goldberg EM1, Zara F1, Lal D1, May P1, Muhle H1, Helbig I1, Weber Y1


Background and objectives: KCNC2 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.

Methods: Individuals with KCNC2 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 Xenopus laevis oocytes.

Results: We identified novel KCNC2 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.

Discussion: These findings implicate KCNC2 as a novel causative gene for epilepsy and emphasize the critical role of KV3.2 in the regulation of brain excitability.