Neurodevelopmental and Epilepsy Phenotypes in Individuals With Missense Variants in the Voltage-Sensing and Pore Domains of <i>KCNH5</i>
Hannah C. Happ, Lynette G. Sadleir, Matthew Zemel, Guillem de Valles‐Ibáñez, Michael S. Hildebrand, Allyn McConkie‐Rosell, Marie McDonald, Halie May, Tristan T. Sands, Vimla S. Aggarwal, Christopher Elder, Timothy Feyma, Allan Bayat, Rikke S. Møller, Christina Fenger, Jens Erik Nielsen, Anita Datta, Kathleen M. Gorman, Mary D. King, Natália 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, Gaëtan Lesca, Pierre Szepetowski, Ingrid E. Scheffer, Heather C. Mefford, Gemma L. Carvill
Abstract
BACKGROUND AND OBJECTIVES: variants. METHODS: 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: as implicated in a spectrum of neurodevelopmental disorders and epilepsy.