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. 2023 Feb 7;100(6):e603-e615.
doi: 10.1212/WNL.0000000000201492. Epub 2022 Oct 28.

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

Hannah C Happ  1   2   3 , Lynette G Sadleir  1   2   3 , Matthew Zemel  1   2   3 , Guillem de Valles-Ibáñez  1   2   3 , Michael S Hildebrand  1   2   3 , Allyn McConkie-Rosell  1   2   3 , Marie McDonald  1   2   3 , Halie May  1   2   3 , Tristan Sands  1   2   3 , Vimla Aggarwal  1   2   3 , Christopher Elder  1   2   3 , Timothy Feyma  1   2   3 , Allan Bayat  1   2   3 , Rikke S Møller  1   2   3 , Christina D Fenger  1   2   3 , Jens Erik Klint Nielsen  1   2   3 , Anita N Datta  1   2   3 , Kathleen M Gorman  1   2   3 , Mary D King  1   2   3 , Natalia D Linhares  1   2   3 , Barbara K Burton  1   2   3 , Andrea Paras  1   2   3 , Sian Ellard  1   2   3 , Julia Rankin  1   2   3 , Anju Shukla  1   2   3 , Purvi Majethia  1   2   3 , Rory J Olson  1   2   3 , Karthik Muthusamy  1   2   3 , Lisa A Schimmenti  1   2   3 , Keith Starnes  1   2   3 , Lucie Sedláčková  1   2   3 , Katalin Štěrbová  1   2   3 , Markéta Vlčková  1   2   3 , Petra Laššuthová  1   2   3 , Alena Jahodová  1   2   3 , Brenda E Porter  1   2   3 , Nathalie Couque  1   2   3 , Estelle Colin  1   2   3 , Clément Prouteau  1   2   3 , Corinne Collet  1   2   3 , Thomas Smol  1   2   3 , Roseline Caumes  1   2   3 , Fleur Vansenne  1   2   3 , Francesca Bisulli  1   2   3 , Laura Licchetta  1   2   3 , Richard Person  1   2   3 , Erin Torti  1   2   3 , Kirsty McWalter  1   2   3 , Richard Webster  1   2   3 , Elizabeth E Gerard  1   2   3 , Gaetan Lesca  1   2   3 , Pierre Szepetowski  1   2   3 , Ingrid E Scheffer  1   2   3 , Heather C Mefford  1   2   3 , Gemma L Carvill  4   5   6
Affiliations

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

Hannah C Happ et al. Neurology. .

Abstract

Background and objectives: KCNH5 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.

Methods: We 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.

Results: We 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.

Discussion: We 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.

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Figures

Figure 1
Figure 1. Location and Conservation of the 6 Unique De Novo KCNH5 Missense Variants
(A) Schematic of Kv10.2 (EAG2), modified from Protter plot of Q8NCM2 (KCNH5_Human). Of the 6 transmembrane domains, S1-S4 make up the voltage-sensing domain, and S5-6 form the pore helix. The KCNH5 patient-specific variants identified in this study are indicated by their amino acid change. (B) Graph of missense tolerance ratio (MTR; y-axis) and protein position (x-axis), with variants indicated. MTR is a measure of protein-encoding cDNA sequence intolerance to missense variants. Variant positions with a value greater than 1 (blue line) is considered neutral; values below 1 are under constraint. Two variants (p.Arg327His and p.Arg333His) are in the 5th percentile of least tolerated missense alterations in the exome. The 5th and 25th percentiles are highlighted in red and yellow, respectively. (C) Locations of variants (color coded) are mapped onto the crystal structure of homotetrameric assembly of Kv10.1 (PDB5K7L); all variants are perfectly conserved between KCNH5 and KCNH1 and are mapped to the corresponding amino acid. The pore domain is highlighted in white, and a single tetrameric subunit is colored light blue. EAG = ether-a-go-go
Figure 2
Figure 2. Phenotypic Spectrum Associated With KCNH5 Missense Variants
The number of individuals in the phenotype group is represented by circle size, and colors of each circle and star match the variant/phenotype class. The individuals with the p.Lys324Glu and p.Arg327His variants in the S4 transmembrane domain presented with an infantile-onset DEE with drug-resistant generalized and focal seizures, whereas the 4 individuals with the nearby recurrent p.Arg333His variant had drug-responsive seizures and became seizure-free. The 2 individuals with variants in or directly at the junction of the S6 transmembrane domain (p.Ile463Thr and p.Thr468Pro) are the most severely affected with a neonatal-onset movement disorder and early-infantile DEE. The single individual with the nearby p.Phe471Ser variant was less severely affected with moderate ID and drug-responsive seizures. Range is indicated in parentheses where applicable. DE = developmental encephalopathy; DEE = developmental and epileptic encephalopathy.
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References

    1. Bauer CK, Schwarz JR. Ether-a-go-go K(+) channels: effective modulators of neuronal excitability. J Physiol. 2018;596(5):769-783. doi: 10.1113/jp275477 - DOI - PMC - PubMed
    1. Simons C, Rash LD, Crawford J, et al. . Mutations in the voltage-gated potassium channel gene KCNH1 cause Temple-Baraitser syndrome and epilepsy. Nat Genet. 2015;47(1):73-77. doi: 10.1038/ng.3153 - DOI - PubMed
    1. Kortum F, Caputo V, Bauer CK, et al. . Mutations in KCNH1 and ATP6V1B2 cause Zimmermann-Laband syndrome. Nat Genet. 2015;47(6):661-667. doi: 10.1038/ng.3282 - DOI - PubMed
    1. Gripp KW, Smithson SF, Scurr IJ, et al. . Syndromic disorders caused by gain-of-function variants in KCNH1, KCNK4, and KCNN3-a subgroup of K(+) channelopathies. Eur J Hum Genet. 2021;29(9):1384-1395. doi: 10.1038/s41431-021-00818-9 - DOI - PMC - PubMed
    1. Mastrangelo M, Scheffer IE, Bramswig NC, et al. . Epilepsy in KCNH1-related syndromes. Epileptic Disord. 2016;18(2):123-136. doi: 10.1684/epd.2016.0830 - DOI - PubMed

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