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February 07, 2023; 100 (6) Research Article

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

View ORCID ProfileHannah C. Happ, Lynette G. Sadleir, Matthew Zemel, Guillem de Valles-Ibáñez, Michael S. Hildebrand, Allyn McConkie-Rosell, Marie McDonald, Halie May, Tristan Sands, Vimla Aggarwal, Christopher Elder, Timothy Feyma, Allan Bayat, Rikke S. Møller, Christina D. Fenger, Jens Erik Klint Nielsen, Anita N. Datta, Kathleen M. Gorman, Mary D. King, Natalia D. Linhares, Barbara K. Burton, Andrea Paras, Sian Ellard, Julia Rankin, Anju Shukla, Purvi Majethia, Rory J. Olson, Karthik Muthusamy, Lisa A. Schimmenti, Keith Starnes, Lucie Sedláčková, Katalin Štěrbová, Markéta Vlčková, Petra Laššuthová, Alena Jahodová, Brenda E. Porter, Nathalie Couque, Estelle Colin, Clément Prouteau, Corinne Collet, Thomas Smol, Roseline Caumes, Fleur Vansenne, Francesca Bisulli, Laura Licchetta, Richard Person, Erin Torti, Kirsty McWalter, Richard Webster, Elizabeth E. Gerard, Gaetan Lesca, Pierre Szepetowski, Ingrid E. Scheffer, Heather C. Mefford, Gemma L. Carvill
First published October 28, 2022, DOI: https://doi.org/10.1212/WNL.0000000000201492
Hannah C. Happ
*These authors contributed equally as first authors.
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Lynette G. Sadleir
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Matthew Zemel
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Guillem de Valles-Ibáñez
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Michael S. Hildebrand
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Allyn McConkie-Rosell
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Marie McDonald
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Halie May
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Tristan Sands
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Vimla Aggarwal
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Christopher Elder
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Timothy Feyma
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Allan Bayat
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Rikke S. Møller
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Christina D. Fenger
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Jens Erik Klint Nielsen
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Anita N. Datta
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Kathleen M. Gorman
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Mary D. King
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Natalia D. Linhares
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Barbara K. Burton
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Andrea Paras
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Sian Ellard
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Julia Rankin
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Anju Shukla
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Purvi Majethia
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Rory J. Olson
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Karthik Muthusamy
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Lisa A. Schimmenti
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Keith Starnes
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Lucie Sedláčková
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Katalin Štěrbová
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Markéta Vlčková
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Petra Laššuthová
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Alena Jahodová
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Brenda E. Porter
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Nathalie Couque
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Estelle Colin
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Clément Prouteau
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Corinne Collet
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Thomas Smol
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Roseline Caumes
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Fleur Vansenne
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Francesca Bisulli
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Laura Licchetta
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Richard Person
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Erin Torti
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Kirsty McWalter
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Richard Webster
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Elizabeth E. Gerard
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Gaetan Lesca
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Pierre Szepetowski
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Ingrid E. Scheffer
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Heather C. Mefford
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Gemma L. Carvill
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Neurodevelopmental and Epilepsy Phenotypes in Individuals With Missense Variants in the Voltage-Sensing and Pore Domains of KCNH5
Hannah C. Happ, Lynette G. Sadleir, Matthew Zemel, Guillem de Valles-Ibáñez, Michael S. Hildebrand, Allyn McConkie-Rosell, Marie McDonald, Halie May, Tristan Sands, Vimla Aggarwal, Christopher Elder, Timothy Feyma, Allan Bayat, Rikke S. Møller, Christina D. Fenger, Jens Erik Klint Nielsen, Anita N. Datta, Kathleen M. Gorman, Mary D. King, Natalia D. Linhares, Barbara K. Burton, Andrea Paras, Sian Ellard, Julia Rankin, Anju Shukla, Purvi Majethia, Rory J. Olson, Karthik Muthusamy, Lisa A. Schimmenti, Keith Starnes, Lucie Sedláčková, Katalin Štěrbová, Markéta Vlčková, Petra Laššuthová, Alena Jahodová, Brenda E. Porter, Nathalie Couque, Estelle Colin, Clément Prouteau, Corinne Collet, Thomas Smol, Roseline Caumes, Fleur Vansenne, Francesca Bisulli, Laura Licchetta, Richard Person, Erin Torti, Kirsty McWalter, Richard Webster, Elizabeth E. Gerard, Gaetan Lesca, Pierre Szepetowski, Ingrid E. Scheffer, Heather C. Mefford, Gemma L. Carvill
Neurology Feb 2023, 100 (6) e603-e615; DOI: 10.1212/WNL.0000000000201492

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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.

Glossary

ACMG=
American College of Medical Genetics and Genomics;
DEE=
developmental and epileptic encephalopathy;
EAG=
ether-a-go-go;
ID=
intellectual disability;
GOF=
gain of function;
MIP=
molecular inversion probe;
NDD=
neurodevelopmental disorder;
VUS=
variants of uncertain significance

Footnotes

  • Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • Previously published at medRxiv, https://doi.org/10.1101/2022.04.26.22274147.

  • Submitted and externally peer reviewed. The handling editor was Renee Shellhaas, MD, MS.

  • Received April 28, 2022.
  • Accepted in final form September 14, 2022.
  • © 2022 American Academy of Neurology
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