KCNT2-related disorders: phenotypes, functional and pharmacological properties.

Apr 17, 2023

Contributors: Maria Cristina Cioclu,Ilaria Mosca,Paolo Ambrosino,Deborah Puzo,Allan Bayat,Saskia B Wortmann,Johannes Koch,Vincent Strehlow,Kentaro Shirai,Naomichi Matsumoto,Stephan J Sanders,Vincent Michaud,Marine Legendre,Antonella Riva,Pasquale Striano,Hiltrud Muhle,Manuela Pendziwiat,Gaetan Lesca,Giuseppe Donato Mangano,Rosaria Nardello, ,Johannes R Lemke,Rikke S Møller,Maria Virginia Soldovieri,Guido Rubboli,Maurizio Taglialatela

Pathogenic variants in KCNT2 are rare causes of developmental epileptic encephalopathy (DEE). We herein describe the phenotypic and genetic features of patients with KCNT2-related DEE, and the in vitro functional and pharmacological properties of KCNT2 channels carrying fourteen novel or previously untested variants.
25 patients harbouring KCNT2 variants were investigated: 12 were identified through an international collaborative network, 13 were retrieved from the literature. Clinical data were collected and included in a standardized phenotyping sheet. Novel variants were detected using exome sequencing and classified using ACMG criteria. Functional and pharmacological studies were performed by whole-cell electrophysiology in HEK-293 cells.
The phenotypic spectrum encompassed: a) Intellectual disability/Developmental delay (21/22 individuals with available information), ranging from mild to severe/profound; b) epilepsy (15/25); c) neurological impairment, with altered muscle tone (14/22); d) dysmorphisms (13/20). Nineteen pathogenic KCNT2 variants were found (nine new, ten reported previously): 16 missense, one in-frame deletion of a single amino acid, one nonsense, and one frameshift. Among tested variants, eight showed gain-of-function (GoF), and six loss-of-function (LoF) features when expressed heterologously in vitro. Quinidine and fluoxetine blocked all GoF variants, whereas loxapine and riluzole activated some LoF variants while blocking others.
We expanded the phenotypic and genotypic spectrum of KCNT2-related disorders, highlighting novel genotype-phenotype associations. Pathogenic KCNT2 variants cause GoF or LoF in vitro phenotypes, and each shows a unique pharmacological profile, suggesting the need for in vitro functional and pharmacological investigation to enable targeted therapies based on the molecular phenotype. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

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ABOUT THE CONTRIBUTORS

Maria Cristina Cioclu,Ilaria Mosca,Paolo Ambrosino,Deborah Puzo,Allan Bayat,Saskia B Wortmann,Johannes Koch,Vincent Strehlow,Kentaro Shirai,Naomichi Matsumoto,Stephan J Sanders,Vincent Michaud,Marine Legendre,Antonella Riva,Pasquale Striano,Hiltrud Muhle,Manuela Pendziwiat,Gaetan Lesca,Giuseppe Donato Mangano,Rosaria Nardello, ,Johannes R Lemke,Rikke S Møller,Maria Virginia Soldovieri,Guido Rubboli,Maurizio Taglialatela
Maria Cristina Cioclu

Department of Epilepsy Genetics and Personalized Medicine (member of ERN EpiCARE), Danish Epilepsy Centre, Filadelfia, Dianalund, Denmark.

Department of Biomedical, Metabolic, and Neural Science, University of Modena and Reggio Emilia, Modena, Italy.

Ilaria Mosca

Department of Medicine and Health Sciences “Vincenzo Tiberio”, University of Molise, Campobasso, Italy.

Paolo Ambrosino

Dept. of Science and Technology, University of Sannio, Benevento, Italy.

Deborah Puzo

Department of Medicine and Health Sciences “Vincenzo Tiberio”, University of Molise, Campobasso, Italy.

Allan Bayat

Department of Epilepsy Genetics and Personalized Medicine (member of ERN EpiCARE), Danish Epilepsy Centre, Filadelfia, Dianalund, Denmark.

Department of Regional Health Research, University of Southern Denmark, Odense, Denmark.

Saskia B Wortmann

University Children’s Hospital, Paracelsus Medical University, Salzburg, Austria.

Amalia Children’s Hospital, Radboudumc, Nijmegen, The Netherlands.

Johannes Koch

University Children’s Hospital, Paracelsus Medical University, Salzburg, Austria.

Vincent Strehlow

Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.

Kentaro Shirai

Department of Pediatrics, Tsuchiura Kyodo General Hospital, Tsuchiura, Ibaraki, 300-0028, Japan.

Naomichi Matsumoto

Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, 236-0004, Japan.

Stephan J Sanders

Department of Psychiatry and Behavioral Sciences, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, California, USA.

Institute for Human Genetics, University of California, San Francisco, San Francisco, California, USA.

Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, California, USA.

Vincent Michaud

Service de Génétique Médicale, Centre de Référence Anomalies du Développement et Syndrome Malformatifs, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, Nouvelle-Aquitaine, France.

Maladies rares: Génétique et Métabolisme (MRGM), INSERM U1211, Université de Bordeaux, Bordeaux, Nouvelle-Aquitaine, France.

Marine Legendre

Service de Génétique Médicale, Centre de Référence Anomalies du Développement et Syndrome Malformatifs, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, Nouvelle-Aquitaine, France.

Antonella Riva

IRCCS Istituto Giannina Gaslini, Genoa, Italy.

Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy.

Pasquale Striano

IRCCS Istituto Giannina Gaslini, Genoa, Italy.

Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy.

Hiltrud Muhle

Department of Neuropediatrics, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, Germany.

Manuela Pendziwiat

Department of Neuropediatrics, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, Germany.

Gaetan Lesca

Department of Medical Genetics, University Hospital of Lyon and Claude Bernard Lyon I University, Lyon, France.

Pathophysiology and Genetics of Neuron and Muscle (PNMG), UCBL, CNRS UMR5261 – INSERM U1315, Lyon, France.

Giuseppe Donato Mangano

Department of Biomedicine, Neuroscience and Advanced Diagnostics, University of Palermo, Palermo, Italy.

Rosaria Nardello

Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties “G. D’Alessandro”, University of Palermo, Palermo, Italy.

Johannes R Lemke

Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.

Center for Rare Diseases, University of Leipzig Medical Center, Leipzig, Germany.

Rikke S Møller

Department of Epilepsy Genetics and Personalized Medicine (member of ERN EpiCARE), Danish Epilepsy Centre, Filadelfia, Dianalund, Denmark.

Department of Regional Health Research, University of Southern Denmark, Odense, Denmark.

Maria Virginia Soldovieri

Department of Medicine and Health Sciences “Vincenzo Tiberio”, University of Molise, Campobasso, Italy.

Guido Rubboli

Department of Epilepsy Genetics and Personalized Medicine (member of ERN EpiCARE), Danish Epilepsy Centre, Filadelfia, Dianalund, Denmark.

University of Copenhagen, Copenhagen, Denmark.

Maurizio Taglialatela

Department of Neuroscience, University of Naples “Federico II”, Naples, Italy.