Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With Epilepsy With KCNC2 Pathogenic Variants.
Schwarz, Niklas; Seiffert, Simone; Pendziwiat, Manuela; Rademacher, Annika Verena; Brà Nger, 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, Leijla; 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
(2022) Neurology, volume 98, issue 20, pp. e2046 - e2059
(Article)
Abstract
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
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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 K V3.2 in the regulation of brain excitability.
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Keywords: Epilepsy, Generalized/genetics, Epilepsy/genetics, Humans, Phenotype, Seizures/genetics, Shaw Potassium Channels/genetics, Whole Exome Sequencing, Clinical Neurology, Journal Article
ISSN: 0028-3878
Publisher: Lippincott Williams and Wilkins
Note: Funding Information: The Article Processing Charge was funded by the authors. Funding Information: The authors thank the participants and their family members for taking part in the study; the Epi25 principal investigators, local staff from individual cohorts, and the patients with epilepsy who participated in the study; and the Stanley Center for Psychiatric Research at the Broad Institute for supporting the genomic data generation efforts and control sample aggregation. The ITAUBG centre thanks Dr Pippucci for supervision in genetic data analysis, the Neurogenetics Laboratory staff (led by Prof. Carelli V), and all the physicians and nurses of the Epilepsy Centre from the Bellaria Hospital in Bologna. This work is part of the Centers for Common Disease Genomics (CCDG) program, funded by the National Human Genome Research Institute (NHGRI) and the National Heart, Lung, and Blood Institute (NHLBI). CCDG-funded Epi25 research activities at the Broad Institute, including genomic data generation in the Broad Genomics Platform, are supported by NHGRI grant UM1 HG008895 (PIs: Eric Lander, Stacey Gabriel, Mark Daly, Sekar Kathiresan). The Genome Sequencing Program efforts were also supported by NHGRI grant 5U01HG009088-02. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Publisher Copyright: © American Academy of Neurology.
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