Missense variants in the voltage sensing and pore domain of KCNH5 cause neurodevelopmental phenotypes including epilepsy

Objective 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 (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. Results We 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. Conclusions We 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. ### Competing Interest Statement L.G.S is a consultant for the Epilepsy Consortium and has received travel grants from Seqirus and Nutricia. She has received research grants and consultancy fees from Zynerba Pharmaceuticals. She has served on an Eisai Pharmaceuticals scientific advisory panel. R.P., E.T., and K.Mc. are employees of GeneDx. B.K.B has received consulting fees and/or honoraria from Aeglea, Alexion, Applied Therapeutics, Biomarin, Capsida, Denali, Horizon, JCR Pharma, Moderna, SIO, Takeda and Ultragenyx and has conducted clinical trials funded by Biomarin, Denali, JCR Pharma, Homology Medicines, Sangamo and Ultragenyx. I.E.S has served on scientific advisory boards for BioMarin, Chiesi, Eisai, Encoded Therapeutics, GlaxoSmithKline, Knopp Biosciences, Nutricia, Rogcon, Takeda Pharmaceuticals, UCB, Xenon Pharmaceuticals; has received speaker honoraria from GlaxoSmithKline, UCB, BioMarin, Biocodex, Chiesi, Liva Nova and Eisai; has received funding for travel from UCB, Biocodex, GlaxoSmithKline, Biomarin and Eisai; has served as an investigator for Anavex Life Sciences, Cerecin Inc, Cereval Therapeutics, Eisai, Encoded Therapeutics, EpiMinder Inc, Epygenyx, ES-Therapeutics, GW Pharma, Marinus, Neurocrine BioSciences, Ovid Therapeutics, Takeda Pharmaceuticals, UCB, Ultragenyx, Xenon Pharmaceutical, Zogenix and Zynerba; and has consulted for Atheneum Partners, Care Beyond Diagnosis, Epilepsy Consortium, Ovid Therapeutics, UCB and Zynerba Pharmaceuticals; and is a Non-Executive Director of Bellberry Ltd and a Director of the Australian Academy of Health and Medical Sciences and the Australian Council of Learned Academies Limited. She may accrue future revenue on pending patent WO61/010176 (filed: 2008): Therapeutic Compound; has a patent for SCN1A testing held by Bionomics Inc and licensed to various diagnostic companies; has a patent molecular diagnostic/theranostic target for benign familial infantile epilepsy (BFIE) [PRRT2] 2011904493 & 2012900190 and PCT/AU2012/001321 (TECH ID:2012-009). The remaining authors have nothing to disclose. ### Funding Statement This work was supported by funding from the NIH (NINDS NS069605). H.C.M is a recipient of the Burroughs Wellcome Fund Career Award for Medical Scientists. G.L.C was funded by the Citizens United for Research in Epilepsy (CURE) Taking Flight Award and NIH (NINDS NS089858). I.E.S is supported by a National Health and Medical Research Council of Australia (NHMRC) Program grant, Investigator grant, Centre of Research Excellence and Synergy grant. L.G.S and G.V.I were supported by Health Research Council of New Zealand and Cure Kids research grants. L.S., K.S., M.V., P.L., A.J. are supported by the Ministry of Health of the Czech Republic AZV NU20-04-00279. CCDG-funded Epi25 research activities at the Broad Institute, including genomic data generation in the Broad Genomics Platform, are supported by NHGRI grant UM1 HG008895 (PIs: Eric Lander, Stacey Gabriel, Mark Daly, Sekar Kathiresan). The Genome Sequencing Program efforts were also supported by NHGRI grant 5U01HG009088-02. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the Austin Health Human Research Ethics Committee, the New Zealand Health and Disability Ethics committee and University Hospital of Lyon and Aix-Marseille University in France Ethics committee. Written informed consent was provided by the patient or their parent or legal guardian in the case of minors or those with intellectual disability. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present work are contained in the manuscript