Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With Epilepsy With KCNC2 Pathogenic Variants.
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Schwarz Niklas, Seiffert Simone, Pendziwiat Manuela, Rademacher Annika Verena, Brünger Tobias, Hedrich Ulrike B S, Augustijn Paul B, Baier Hartmut, Bayat Allan, Bisulli Francesca, Buono Russell J, Bruria Ben Zeev, Doyle Michael G, Guerrini Renzo, Heimer Gali, Iacomino Michele, Kearney Hugh, Klein Karl Martin, Kousiappa Ioanna, Kunz Wolfram S, Lerche Holger, Licchetta Laura, Lohmann Ebba, Minardi Raffaella, McDonald Marie, Montgomery Sarah, Mulahasanovic Lejla, Oegema Renske, Ortal Barel, Papacostas Savvas S, Ragona Francesca, Granata Tiziana, Reif Phillip S, Rosenow Felix, Rothschild Annick, Scudieri Paolo, Striano Pasquale, Tinuper Paolo, Tanteles George A, Vetro Annalisa, Zahnert Felix, Goldberg Ethan M, Zara Federico, Lal Dennis, May Patrick, Muhle Hiltrud, Helbig Ingo, Weber Yvonne
Аннотация
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.