Missense variants in the voltage sensing and pore domain of KCNH5 cause neurodevelopmental phenotypes including epilepsy
Authors: Happ Hannah C. , 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. , Nielsen Jens Erik Klint , Datta Anita N. , Gorman Kathleen M. , King Mary D. , Linhares Natalia , 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 , Lesca Gaetan , Szepetowski Pierre , Scheffer Ingrid E. , Mefford Heather C. , Carvill Gemma L. 
Published: April 2022

AbstractObjectiveKCNH5 encodes the voltage-gated potassium channel EAG2/Kv10.2. We aimed to delineate the neurodevelopmental and epilepsy phenotypic spectrum associated with de novo KCNH5 variants.MethodsWe screened 893 individuals with developmental and epileptic encephalopathies (DEEs) for KCNH5 variants using targeted or exome sequencing. Additional individuals with KCNH5 variants were identified through an international collaboration. Clinical history, EEG, and imaging data were analyzed; seizure types and epilepsy syndromes were classified. We included three previously published individuals including additional phenotypic details.ResultsWe report a cohort of 17 patients, including nine with a recurrent de novo missense variant p.Arg327His, four with a recurrent missense variant p.Arg333His, and four 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 American College of Medical Genetics and Genomics (ACMG) criteria. All individuals presented with epilepsy with a median seizure onset at six 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 generalised epilepsy and normal intellect, while the recurrent p.Arg327His variant was associated with infantile-onset DEE. Two individuals with variants in the pore-domain were more severely affected, with neonatal-onset DEE, profound disability, and childhood death.ConclusionsWe report the first 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 establish KCNH5 as implicated in a spectrum of neurodevelopmental disorders (NDDs) and epilepsy.