Neurodevelopmental and Epilepsy Phenotypes in Individuals With Missense Variants in the Voltage-Sensing and Pore Domains ofKCNH5
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Published:2022-10-28
Issue:6
Volume:100
Page:e603-e615
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ISSN:0028-3878
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Container-title:Neurology
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language:en
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Short-container-title:Neurology
Author:
Happ Hannah C.ORCID, Sadleir Lynette G., Zemel Matthew, de Valles-Ibáñez Guillem, Hildebrand Michael S., McConkie-Rosell Allyn, McDonald Marie, May Halie, Sands Tristan, Aggarwal Vimla, Elder Christopher, Feyma Timothy, Bayat Allan, Møller Rikke S., Fenger Christina D., Klint Nielsen Jens Erik, Datta Anita N., Gorman Kathleen M., King Mary D., Linhares Natalia D., Burton Barbara K., Paras Andrea, Ellard Sian, Rankin Julia, Shukla Anju, Majethia Purvi, Olson Rory J., Muthusamy Karthik, Schimmenti Lisa A., Starnes Keith, Sedláčková Lucie, Štěrbová Katalin, Vlčková Markéta, Laššuthová Petra, Jahodová Alena, Porter Brenda E., Couque Nathalie, Colin Estelle, Prouteau Clément, Collet Corinne, Smol Thomas, Caumes Roseline, Vansenne Fleur, Bisulli Francesca, Licchetta Laura, Person Richard, Torti Erin, McWalter Kirsty, Webster Richard, Gerard Elizabeth E., Lesca Gaetan, Szepetowski Pierre, Scheffer Ingrid E., Mefford Heather C., Carvill Gemma L.
Abstract
Background and ObjectivesKCNH5encodes the voltage-gated potassium channel EAG2/Kv10.2. We aimed to delineate the neurodevelopmental and epilepsy phenotypic spectrum associated with de novoKCNH5variants.MethodsWe screened 893 individuals with developmental and epileptic encephalopathies forKCNH5variants using targeted or exome sequencing. Additional individuals withKCNH5variants were identified through an international collaboration. Clinical history, EEG, and imaging data were analyzed; seizure types and epilepsy syndromes were classified. We included 3 previously published individuals including additional phenotypic details.ResultsWe report a cohort of 17 patients, including 9 with a recurrent de novo missense variant p.Arg327His, 4 with a recurrent missense variant p.Arg333His, and 4 additional novel missense variants. All variants were located in or near the functionally critical voltage-sensing or pore domains, absent in the general population, and classified as pathogenic or likely pathogenic using the American College of Medical Genetics and Genomics criteria. All individuals presented with epilepsy with a median seizure onset at 6 months. They had a wide range of seizure types, including focal and generalized seizures. Cognitive outcomes ranged from normal intellect to profound impairment. Individuals with the recurrent p.Arg333His variant had a self-limited drug-responsive focal or generalized epilepsy and normal intellect, whereas the recurrent p.Arg327His variant was associated with infantile-onset DEE. Two individuals with variants in the pore domain were more severely affected, with a neonatal-onset movement disorder, early-infantile DEE, profound disability, and childhood death.DiscussionWe describe a cohort of 17 individuals with pathogenic or likely pathogenic missense variants in the voltage-sensing and pore domains of Kv10.2, including 14 previously unreported individuals. We present evidence for a putative emerging genotype-phenotype correlation with a spectrum of epilepsy and cognitive outcomes. Overall, we expand the role of EAG proteins in human disease and establishKCNH5as implicated in a spectrum of neurodevelopmental disorders and epilepsy.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Neurology (clinical)
Cited by
2 articles.
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