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Novel KCNH1 Mutations Associated with Epilepsy: Broadening the Phenotypic Spectrum of KCNH1-Associated Diseases

Here, we describe four patients suffering from a rather broad spectrum of epilepsy-related disorders, ranging from developmental and epileptic encephalopathy with intellectual disability (DEE) to genetic generalized epilepsy (GGE), which all harbor novel KCNH1 mutations. In one family, we found a we...

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Autores principales: von Wrede, Randi, Jeub, Monika, Ariöz, Idil, Elger, Christian E., von Voss, Hubertus, Klein, Hanns-Georg, Becker, Albert J., Schoch, Susanne, Surges, Rainer, Kunz, Wolfram S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909785/
https://www.ncbi.nlm.nih.gov/pubmed/33494179
http://dx.doi.org/10.3390/genes12020132
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author von Wrede, Randi
Jeub, Monika
Ariöz, Idil
Elger, Christian E.
von Voss, Hubertus
Klein, Hanns-Georg
Becker, Albert J.
Schoch, Susanne
Surges, Rainer
Kunz, Wolfram S.
author_facet von Wrede, Randi
Jeub, Monika
Ariöz, Idil
Elger, Christian E.
von Voss, Hubertus
Klein, Hanns-Georg
Becker, Albert J.
Schoch, Susanne
Surges, Rainer
Kunz, Wolfram S.
author_sort von Wrede, Randi
collection PubMed
description Here, we describe four patients suffering from a rather broad spectrum of epilepsy-related disorders, ranging from developmental and epileptic encephalopathy with intellectual disability (DEE) to genetic generalized epilepsy (GGE), which all harbor novel KCNH1 mutations. In one family, we found a weak association of a novel nonsense mutation with epilepsy, suggesting reduced penetrance, and which shows, in agreement with previous findings, that gain-of-function effects rather than haploinsufficiency are important for the pathogenicity of mutations. De novo missense variants in the pore region of the channel result in severe phenotypes presenting usually with DEE with various malformations. The potential pathogenicity of a novel KCNH1 germline mutation located outside of the critical pore domain observed in a GGE patient with a milder phenotype is supported by the fact that the very same amino acid exchange was detected as a somatic mutation in the resected brain tissue of a patient suffering from a focal cortical dysplasia type IIb. Thus, our case series broadens the phenotypic spectrum of KCNH1-associated diseases.
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spelling pubmed-79097852021-02-27 Novel KCNH1 Mutations Associated with Epilepsy: Broadening the Phenotypic Spectrum of KCNH1-Associated Diseases von Wrede, Randi Jeub, Monika Ariöz, Idil Elger, Christian E. von Voss, Hubertus Klein, Hanns-Georg Becker, Albert J. Schoch, Susanne Surges, Rainer Kunz, Wolfram S. Genes (Basel) Article Here, we describe four patients suffering from a rather broad spectrum of epilepsy-related disorders, ranging from developmental and epileptic encephalopathy with intellectual disability (DEE) to genetic generalized epilepsy (GGE), which all harbor novel KCNH1 mutations. In one family, we found a weak association of a novel nonsense mutation with epilepsy, suggesting reduced penetrance, and which shows, in agreement with previous findings, that gain-of-function effects rather than haploinsufficiency are important for the pathogenicity of mutations. De novo missense variants in the pore region of the channel result in severe phenotypes presenting usually with DEE with various malformations. The potential pathogenicity of a novel KCNH1 germline mutation located outside of the critical pore domain observed in a GGE patient with a milder phenotype is supported by the fact that the very same amino acid exchange was detected as a somatic mutation in the resected brain tissue of a patient suffering from a focal cortical dysplasia type IIb. Thus, our case series broadens the phenotypic spectrum of KCNH1-associated diseases. MDPI 2021-01-21 /pmc/articles/PMC7909785/ /pubmed/33494179 http://dx.doi.org/10.3390/genes12020132 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
von Wrede, Randi
Jeub, Monika
Ariöz, Idil
Elger, Christian E.
von Voss, Hubertus
Klein, Hanns-Georg
Becker, Albert J.
Schoch, Susanne
Surges, Rainer
Kunz, Wolfram S.
Novel KCNH1 Mutations Associated with Epilepsy: Broadening the Phenotypic Spectrum of KCNH1-Associated Diseases
title Novel KCNH1 Mutations Associated with Epilepsy: Broadening the Phenotypic Spectrum of KCNH1-Associated Diseases
title_full Novel KCNH1 Mutations Associated with Epilepsy: Broadening the Phenotypic Spectrum of KCNH1-Associated Diseases
title_fullStr Novel KCNH1 Mutations Associated with Epilepsy: Broadening the Phenotypic Spectrum of KCNH1-Associated Diseases
title_full_unstemmed Novel KCNH1 Mutations Associated with Epilepsy: Broadening the Phenotypic Spectrum of KCNH1-Associated Diseases
title_short Novel KCNH1 Mutations Associated with Epilepsy: Broadening the Phenotypic Spectrum of KCNH1-Associated Diseases
title_sort novel kcnh1 mutations associated with epilepsy: broadening the phenotypic spectrum of kcnh1-associated diseases
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909785/
https://www.ncbi.nlm.nih.gov/pubmed/33494179
http://dx.doi.org/10.3390/genes12020132
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