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

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. KunzHolger 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^*

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

Abstract

Background and ObjectivesKCNC2 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.MethodsIndividuals 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.ResultsWe 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.DiscussionThese findings implicate KCNC2 as a novel causative gene for epilepsy and emphasize the critical role of KV3.2 in the regulation of brain excitability.

Original language	English
Pages (from-to)	E2046-E2059
Journal	Neurology
Volume	98
Issue number	20
DOIs	https://doi.org/10.1212/WNL.0000000000200660
State	Published - 17 May 2022

Funding

Funders	Funder number
Epilepsy NeuroGenetics Initiative
National Institutes of Health
National Heart, Lung, and Blood Institute
National Human Genome Research Institute
National Institute of Neurological Disorders and Stroke	U54 NS108874, K02NS112600
National Institute of Neurological Disorders and Stroke
National Center for Advancing Translational Sciences	UL1TR001878
National Center for Advancing Translational Sciences
Children's Hospital of Philadelphia
Hartwell Foundation
University of Pennsylvania	U54 HD086984
University of Pennsylvania
Intellectual and Developmental Disabilities Research Center
Perelman School of Medicine, University of Pennsylvania
Institute for Translational Medicine and Therapeutics
Eunice Kennedy Shriver National Institute of Child Health and Human Development
Broad Institute	5U01HG009088-02, UM1 HG008895
Broad Institute
Science Foundation Ireland	16/RC/3948
Science Foundation Ireland
Bundesministerium für Bildung und Forschung	01GM1907
Bundesministerium für Bildung und Forschung
Christian-Albrechts-Universität zu Kiel
Ministero della Salute
European Regional Development Fund
Regione Toscana

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1212/WNL.0000000000200660

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Schwarz, N., Seiffert, S., Pendziwiat, M., Rademacher, A. V., Brünger, T., Hedrich, U. B. S., Augustijn, P. B., Baier, H., Bayat, A., Bisulli, F., Buono, R. J., Bruria, B. Z., Doyle, M. G., Guerrini, R., Heimer, G., Iacomino, M., Kearney, H., Klein, K. M., Kousiappa, I., ... Weber, Y. (2022). Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With Epilepsy With KCNC2 Pathogenic Variants. Neurology, 98(20), E2046-E2059. https://doi.org/10.1212/WNL.0000000000200660

@article{7da6bb3945d34c09b2c0c6fb4ed771aa,

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

abstract = "Background and ObjectivesKCNC2 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.MethodsIndividuals 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.ResultsWe 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.DiscussionThese findings implicate KCNC2 as a novel causative gene for epilepsy and emphasize the critical role of KV3.2 in the regulation of brain excitability.",

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

note = "Publisher Copyright: {\textcopyright} American Academy of Neurology.",

year = "2022",

month = may,

day = "17",

doi = "10.1212/WNL.0000000000200660",

language = "אנגלית",

volume = "98",

pages = "E2046--E2059",

journal = "Neurology",

issn = "0028-3878",

publisher = "Lippincott Williams and Wilkins Ltd.",

number = "20",

}

Schwarz, N, Seiffert, S, Pendziwiat, M, Rademacher, AV, Brünger, T, Hedrich, UBS, Augustijn, PB, Baier, H, Bayat, A, Bisulli, F, Buono, RJ, Bruria, BZ, Doyle, MG, Guerrini, R, Heimer, G, Iacomino, M, Kearney, H, Klein, KM, Kousiappa, I, Kunz, WS, Lerche, H, Licchetta, L, Lohmann, E, Minardi, R, McDonald, M, Montgomery, S, Mulahasanovic, L, Oegema, R, Ortal, B, Papacostas, SS, Ragona, F, Granata, T, Reif, PS, Rosenow, F, Rothschild, A, Scudieri, P, Striano, P, Tinuper, P, Tanteles, GA, Vetro, A, Zahnert, F, Goldberg, EM, Zara, F, Lal, D, May, P, Muhle, H, Helbig, I & Weber, Y 2022, 'Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With Epilepsy With KCNC2 Pathogenic Variants', Neurology, vol. 98, no. 20, pp. E2046-E2059. https://doi.org/10.1212/WNL.0000000000200660

TY - JOUR

T1 - Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With Epilepsy With KCNC2 Pathogenic Variants

AU - Schwarz, Niklas

AU - Seiffert, Simone

AU - Pendziwiat, Manuela

AU - Rademacher, Annika Verena

AU - Brünger, Tobias

AU - Hedrich, Ulrike B.S.

AU - Augustijn, Paul B.

AU - Baier, Hartmut

AU - Bayat, Allan

AU - Bisulli, Francesca

AU - Buono, Russell J.

AU - Bruria, Ben Zeev

AU - Doyle, Michael G.

AU - Guerrini, Renzo

AU - Heimer, Gali

AU - Iacomino, Michele

AU - Kearney, Hugh

AU - Klein, Karl Martin

AU - Kousiappa, Ioanna

AU - Kunz, Wolfram S.

AU - Lerche, Holger

AU - Licchetta, Laura

AU - Lohmann, Ebba

AU - Minardi, Raffaella

AU - McDonald, Marie

AU - Montgomery, Sarah

AU - Mulahasanovic, Lejla

AU - Oegema, Renske

AU - Ortal, Barel

AU - Papacostas, Savvas S.

AU - Ragona, Francesca

AU - Granata, Tiziana

AU - Reif, Phillip S.

AU - Rosenow, Felix

AU - Rothschild, Annick

AU - Scudieri, Paolo

AU - Striano, Pasquale

AU - Tinuper, Paolo

AU - Tanteles, George A.

AU - Vetro, Annalisa

AU - Zahnert, Felix

AU - Goldberg, Ethan M.

AU - Zara, Federico

AU - Lal, Dennis

AU - May, Patrick

AU - Muhle, Hiltrud

AU - Helbig, Ingo

AU - Weber, Yvonne

PY - 2022/5/17

Y1 - 2022/5/17

N2 - Background and ObjectivesKCNC2 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.MethodsIndividuals 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.ResultsWe 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.DiscussionThese findings implicate KCNC2 as a novel causative gene for epilepsy and emphasize the critical role of KV3.2 in the regulation of brain excitability.

AB - Background and ObjectivesKCNC2 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.MethodsIndividuals 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.ResultsWe 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.DiscussionThese findings implicate KCNC2 as a novel causative gene for epilepsy and emphasize the critical role of KV3.2 in the regulation of brain excitability.

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SN - 0028-3878

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JO - Neurology

JF - Neurology

IS - 20

ER -

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

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