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

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11130%2F23%3A10449335" target="_blank" >RIV/00216208:11130/23:10449335 - isvavai.cz</a>

Alternative codes found

RIV/00064203:_____/23:10449335

Result on the web

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=FGS8r7_6kh" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=FGS8r7_6kh</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1212/WNL.0000000000201492" target="_blank" >10.1212/WNL.0000000000201492</a>

Result language

angličtina

Original language name

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

Original language description

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 generalized 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 a neonatal-onset movement disorder, early-infantile 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.

Czech name

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Czech description

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Type

J_SC - Article in a specialist periodical, which is included in the SCOPUS database

CEP classification

—

OECD FORD branch

30103 - Neurosciences (including psychophysiology)

Project

<a href="/en/project/NU20-04-00279" target="_blank" >NU20-04-00279: Epilepsy genetics: To solve unsolvable cases with combined OMICs tools</a><br>

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2023

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Neurology

ISSN

0028-3878

e-ISSN

1526-632X

Volume of the periodical

100

Issue of the periodical within the volume

6

Country of publishing house

US - UNITED STATES

Number of pages

13

Pages from-to

"e603"-"e615"

UT code for WoS article

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EID of the result in the Scopus database

2-s2.0-85145325918