TY - JOUR

T1 - Neurodevelopmental and Epilepsy Phenotypes in Individuals With Missense Variants in the Voltage-Sensing and Pore Domains of KCNH5

AU - Happ, Hannah C.

AU - Sadleir, Lynette G.

AU - Zemel, Matthew

AU - De Valles-Ibáñez, Guillem

AU - Hildebrand, Michael S.

AU - McConkie-Rosell, Allyn

AU - McDonald, Marie

AU - May, Halie

AU - Sands, Tristan

AU - Aggarwal, Vimla

AU - Elder, Christopher

AU - Feyma, Timothy

AU - Bayat, Allan

AU - Møller, Rikke S.

AU - Fenger, Christina D.

AU - Klint Nielsen, Jens Erik

AU - Datta, Anita N.

AU - Gorman, Kathleen M.

AU - King, Mary D.

AU - Linhares, Natalia D.

AU - Burton, Barbara K.

AU - Paras, Andrea

AU - Ellard, Sian

AU - Rankin, Julia

AU - Shukla, Anju

AU - Majethia, Purvi

AU - Olson, Rory J.

AU - Muthusamy, Karthik

AU - Schimmenti, Lisa A.

AU - Starnes, Keith

AU - Sedlacková, Lucie

AU - Štěrbová, Katalin

AU - Vlčková, Markéta

AU - Laššuthová, Petra

AU - Jahodová, Alena

AU - Porter, Brenda E.

AU - Couque, Nathalie

AU - Colin, Estelle

AU - Prouteau, Clément

AU - Collet, Corinne

AU - Smol, Thomas

AU - Caumes, Roseline

AU - Vansenne, Fleur

AU - Bisulli, Francesca

AU - Licchetta, Laura

AU - Person, Richard

AU - Torti, Erin

AU - McWalter, Kirsty

AU - Webster, Richard

AU - Gerard, Elizabeth E.

N1 - Publisher Copyright: © American Academy of Neurology.

PY - 2023

Y1 - 2023

N2 - Background and ObjectivesKCNH5 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 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 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 establish KCNH5 as implicated in a spectrum of neurodevelopmental disorders and epilepsy.

AB - Background and ObjectivesKCNH5 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 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 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 establish KCNH5 as implicated in a spectrum of neurodevelopmental disorders and epilepsy.

U2 - 10.1212/WNL.0000000000201492

DO - 10.1212/WNL.0000000000201492

M3 - Journal article

C2 - 36307226

AN - SCOPUS:85145325918

VL - 100

SP - E603-E615

JO - Neurology

JF - Neurology

SN - 0028-3878

IS - 6

ER -