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

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

doi:10.1212/WNL.0000000000200660

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

Neurology. 2022 May 17;98(20):e2046-e2059. doi: 10.1212/WNL.0000000000200660. Epub 2022 Mar 21.

Authors

Niklas Schwarz¹, Simone Seiffert¹, Manuela Pendziwiat¹, Annika Verena Rademacher¹, Tobias Brünger¹, Ulrike B S Hedrich¹, Paul B Augustijn¹, Hartmut Baier¹, Allan Bayat¹, Francesca Bisulli¹, Russell J Buono¹, Ben Zeev Bruria¹, Michael G Doyle¹, Renzo Guerrini¹, Gali Heimer¹, Michele Iacomino¹, Hugh Kearney¹, Karl Martin Klein¹, Ioanna Kousiappa¹, Wolfram S Kunz¹, Holger Lerche¹, Laura Licchetta¹, Ebba Lohmann¹, Raffaella Minardi¹, Marie McDonald¹, Sarah Montgomery¹, Lejla Mulahasanovic¹, Renske Oegema¹, Barel Ortal¹, Savvas S Papacostas¹, Francesca Ragona¹, Tiziana Granata¹, Phillip S Reif¹, Felix Rosenow¹, Annick Rothschild¹, Paolo Scudieri¹, Pasquale Striano¹, Paolo Tinuper¹, George A Tanteles¹, Annalisa Vetro¹, Felix Zahnert¹, Ethan M Goldberg¹, Federico Zara¹, Dennis Lal¹, Patrick May¹, Hiltrud Muhle¹, Ingo Helbig¹, Yvonne Weber¹

Affiliation

¹ From the Departments of Neurology and Epileptology (N.S., S.S., U.B.S.H., H.L., Y.W.) and Neurodegenerative Diseases (E.L.), Hertie-Institute for Clinical Brain Research, University of Tübingen; Institute of Clinical Molecular Biology (M.P., I.H.), Christian-Albrechts-University of Kiel; Departments of Neuropediatrics (M.P., A.V.R., H.M., I.H.) and Pediatrics I (A.V.R.), University Medical Center Schleswig-Holstein, Christian-Albrechts-University, Kiel; Cologne Center for Genomics (T.B., D.L.), University of Cologne, Germany; Epilepsy Center SEIN (P.B.A.), Heemstede, the Netherlands; Epilepsiezentrum Bodensee (H.B.), Weissenau, Germany; Department of Genetics and Precision Medicine (A.B.), Danish Epilepsy Centre, Dianalund, Denmark; IRCCS Istituti delle Scienze Neurologiche di Bologna (F.B., L.L., R.M., P.T.); Department of Biomedical and Neuromotor Sciences (F.B., L.L., P.T.), University of Bologna, Italy; Department of Biomedical Sciences (R.J.B.), Cooper Medical School of Rowan University, Camden, NJ; Pediatric Neurology Unit (B.Z.B., G.H.), Edmond and Lily Safra Children's Hospital, Chaim Sheba Medical Center, Ramat Gan; Sackler School of Medicine (B.Z.B., G.H.), Tel Aviv University, Israel; FutureNeuro SFI Research Centre (M.G.D., H.K.) and Department of Neurology, Beaumont Hospital (M.G.D., H.K.), Royal College of Surgeons in Ireland; StAR MD Programme (M.G.D.), Royal College of Surgeons in Ireland in collaboration with Blackrock Clinic, Dublin, Ireland; Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, and Department of Neuroscience (R.G., A.V.), A. Meyer Children's Hospital, University of Florence; IRCCS Istituto Giannina Gaslini (M.I., P. Striano), Genova, Italy; Epilepsy Center Frankfurt Rhine-Main, Department of Neurology (K.M.K., P.S.R., F. Rosenow), University Hospital Frankfurt; LOEWE Center for Personalized Translational Epilepsy Research (CePTER) (K.M.K., P.S.R., F. Rosenow), Goethe-University Frankfurt, Germany; Departments of Clinical Neurosciences, Medical Genetics, and Community Health Sciences (K.M.K.), Hotchkiss Brain Institute & Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Canada; Department of Neurobiology and Epilepsy Center (I.K., S.S.P.), The Cyprus Institute of Neurology and Genetics, Nicosia; Institute of Experimental Epileptology and Cognition Research and Department of Epileptology (W.S.K.), University of Bonn, Germany; Division of Medical Genetics, Department of Pediatrics (M.M., S.M.), Duke University, Durham, NC; CeGaT GmbH and Praxis für Humangenetik Tübingen (L.M.), Germany; Division Biomedical Genetics (R.O.), University Medical Center Utrecht, the Netherlands; The Genomic Unit, Sheba Cancer Research Center (B.O.), Cancer Research Center, Wohl Institute for Translational Medicine (B.O.), and The Institute for Rare Diseases, The Edmond and Lily Safra Children's Hospital (A.R.), Sheba Medical Center, Tel Hashomer, Israel; Medical School (S.S.P.), University of Nicosia, Cyprus; Department of Pediatric Neuroscience (F. Ragona, T.G.), Fondazione IRCCS Istituto Neurologico Carlo Besta, Member of the ERN EpiCARE, Milan, Italy; Sheba Medical Center, Tel-Hashomer; Sackler Faculty of Medicine (A.R.), Tel Aviv University, Israel; Departments of Neurosciences, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health (P. Scudieri, P. Striano, F. Zara), University of Genova, Italy; Clinical Genetics and Genomics Department (G.A.T.), The Cyprus Institute of Neurology and Genetics, Nicosia; Department of Neurology (F. Zahnert), Epilepsy Center Hessen, Philipps-University Marburg, Germany; Division of Neurology (E.M.G., I.H.), The Epilepsy NeuroGenetics Initiative (ENGIN) (E.M.G., I.H.), and Department of Biomedical and Health Informatics (DBHi) (I.H.), Children's Hospital of Philadelphia, PA; Epilepsy Center, Neurological Institute (D.L.), and Genomic Medicine Institute, Lerner Research Institute (D.L.), Cleveland Clinic, OH; Stanley Center for Psychiatric Research (D.L.), The Broad Institute of Harvard and MIT, Cambridge, MA; Analytic and Translational Genetics Unit (D.L.), Massachusetts General Hospital, Boston; Luxembourg Centre for Systems Biomedicine (P.M.), University Luxembourg; Department of Neurology (I.H.), Perelman School of Medicine, University of Pennsylvania, PA; and Department of Epileptology and Neurology (Y.W.), University of Aachen, Germany.

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 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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Epilepsy* / genetics
Epilepsy, Generalized* / genetics
Exome Sequencing
Humans
Phenotype
Seizures / genetics
Shaw Potassium Channels / genetics

Substances

KCNC2 protein, human
Shaw Potassium Channels

Abstract

Publication types

MeSH terms

Substances

Grants and funding