Etiological involvement of KCND1 variants in an X-linked neurodevelopmental disorder with variable expressivity

Tassja Kalm; Claudia Schob; Hanna Völler; Thatjana Gardeitchik; Christian Gilissen; Rolph Pfundt; Chiara Klöckner; Konrad Platzer; Annick Klabunde-Cherwon; Markus Ries; Steffen Syrbe; Francesca Beccaria; Francesca Madia; Marcello Scala; Federico Zara; Floris Hofstede; Marleen E.H. Simon; Richard van Jaarsveld; Renske Oegema; Koen L.I. van Gassen; Sjoerd J.B. Holwerda; Tahsin Stefan Barakat; Arjan Bouman; Marjon van Slegtenhorst; Sara Álvarez; Alberto Fernández Jaén; Javier Porta; Andrea Accogli; Margherita Maria Mancardi; Pasquale Striano; Michele Iacomino; Jong-Hee Chae; Sesong Jang; Soo Y. Kim; David Chitayat; Saadet Mercimek-Andrews; Christel Depienne; Antje Kampmeier; Alma Kuechler; Harald Surowy; Enrico Silvio Bertini; Francesca Clementina Radio; Cecilia Mancini; Simone Pizzi; Marco Tartaglia; Lucas Gauthier; David Geneviève; Mylène Tharreau; Noy Azoulay; Gal Zaks Hoffer; Nesia Gilad; Naama Orenstein; Geneviève Bernard; Isabelle Thiffault; Jonas Denecke; Theresia Herget; Fanny Kortüm; Christian Kubisch; Robert Bähring; Stefan Kindler

doi:10.1016/j.ajhg.2024.04.019

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Etiological involvement of KCND1 variants in an X-linked neurodevelopmental disorder with variable expressivity

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Etiological involvement of KCND1 variants in an X-linked neurodevelopmental disorder with variable expressivity

Tassja Kalm, Claudia Schob, Hanna Völler, Thatjana Gardeitchik, Christian Gilissen, Rolph Pfundt, Chiara Klöckner, Konrad Platzer, Annick Klabunde-Cherwon, Markus Ries, …

American Journal of Human Genetics, Vol.111(6), pp.1206-1221

06/2024

DOI: https://doi.org/10.1016/j.ajhg.2024.04.019

PMCID: PMC11179411

PMID: 38772379

Résumé

Utilizing trio whole-exome sequencing and a gene matching approach, we identified a cohort of 18 male individuals from 17 families with hemizygous variants in KCND1, including two de novo missense variants, three maternally inherited protein-truncating variants, and 12 maternally inherited missense variants. Affected subjects present with a neurodevelopmental disorder characterized by diverse neurological abnormalities, mostly delays in different developmental domains, but also distinct neuropsychiatric signs and epilepsy. Heterozygous carrier mothers are clinically unaffected. KCND1 encodes the α-subunit of Kv4.1 voltage-gated potassium channels. All variant-associated amino acid substitutions affect either the cytoplasmic N- or C-terminus of the channel protein except for two occurring in transmembrane segments 1 and 4. Kv4.1 channels were functionally characterized in the absence and presence of auxiliary β subunits. Variant-specific alterations of biophysical channel properties were diverse and varied in magnitude. Genetic data analysis in combination with our functional assessment shows that Kv4.1 channel dysfunction is involved in the pathogenesis of an X-linked neurodevelopmental disorder frequently associated with a variable neuropsychiatric clinical phenotype.

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Titre: Etiological involvement of KCND1 variants in an X-linked neurodevelopmental disorder with variable expressivity
Créateurs - sans rôle: Tassja Kalm - Universität Hamburg
Claudia Schob - University Medical Center Hamburg-Eppendorf
Hanna Völler - University Medical Center Hamburg-Eppendorf
Thatjana Gardeitchik - Radboud University Medical Center
Christian Gilissen - Radboud University Medical Center
Rolph Pfundt - University Medical Center
Chiara Klöckner - Leipzig University
Konrad Platzer - Leipzig University
Annick Klabunde-Cherwon - University Hospital Heidelberg
Markus Ries - Heidelberg University
Steffen Syrbe - University Hospital Heidelberg
Francesca Beccaria - Azienda Socio Sanitaria Territoriale di Mantova [Mantova, Italy]
Francesca Madia - Istituto Giannina Gaslini
Marcello Scala - Istituto Giannina Gaslini
Federico Zara - Istituto Giannina Gaslini
Floris Hofstede - Wilhelmina Children's Hospital
Marleen E.H. Simon - University Medical Center [Utrecht]
Richard van Jaarsveld - University Medical Center Utrecht
Renske Oegema - University Medical Center Utrecht
Koen L.I. van Gassen - University Medical Center Utrecht
Sjoerd J.B. Holwerda - University Medical Center Utrecht
Tahsin Stefan Barakat - Erasmus MC
Arjan Bouman - Erasmus MC
Marjon van Slegtenhorst - Erasmus MC
Sara Álvarez - NIMGenetics
Alberto Fernández Jaén - Universidad Europea de Madrid = European University of Madrid
Javier Porta
Andrea Accogli - McGill University Health Centre
Margherita Maria Mancardi - Istituto Giannina Gaslini
Pasquale Striano - University of Genoa
Michele Iacomino - Istituto Giannina Gaslini
Jong-Hee Chae - Seoul National University
Sesong Jang - Seoul National University
Soo Y. Kim - Seoul National University Hospital
David Chitayat - SickKids Foundation
Saadet Mercimek-Andrews - University of Alberta
Christel Depienne - University of Duisburg-Essen
Antje Kampmeier - University of Duisburg-Essen
Alma Kuechler - University of Duisburg-Essen
Harald Surowy - University of Duisburg-Essen
Enrico Silvio Bertini - Bambino Gesù Children's Hospital
Francesca Clementina Radio - Bambino Gesù Children's Hospital
Cecilia Mancini - Bambino Gesù Children's Hospital
Simone Pizzi - Bambino Gesù Children's Hospital
Marco Tartaglia - Bambino Gesù Children's Hospital
Lucas Gauthier - Centre Hospitalier Universitaire de Montpellier
David Geneviève - Université de Montpellier
Mylène Tharreau - Centre Hospitalier Universitaire de Montpellier
Noy Azoulay - Rabin Medical Center
Gal Zaks Hoffer - Rafael Advanced Defense Systems
Nesia Gilad - Faculty
Naama Orenstein - Tel Aviv University
Geneviève Bernard - McGill University Health Centre
Isabelle Thiffault - University of Missouri–Kansas City
Jonas Denecke - University Medical Center Hamburg-Eppendorf
Theresia Herget - University Medical Center Hamburg-Eppendorf
Fanny Kortüm - University Medical Center Hamburg-Eppendorf
Christian Kubisch - Universität Hamburg
Robert Bähring - Universität Hamburg
Stefan Kindler - University Medical Center Hamburg-Eppendorf
Détails de publication: American Journal of Human Genetics, Vol.111(6), pp.1206-1221
Note de subvention: This work was supported by the Deutsche Forschungsgemeinschaft (BA2055/1-3 and BA2055/6-1 to R.B. and SCHO 1921/2-1 to C.S.), the Netherlands Organisation for Scientific Research (ZonMw Vidi, grant 09150172110002 to T.S.B.), an Erasmus MC Fellowship 2017 (to T.S.B.), the Erasmus MC Human Disease Model Award 2018 (to T.S.B.), PNRR-MUR-M4C2 PE0000006 Research Program ‘‘MNESYS’’ - A multiscale integrated approach to the study of the nervous system in health and disease (to P.S.), the Italian Ministry of Health (CCR-2017-23669081 and RF-2021-12374963 to M.T.). I
Identifiants: 99150735409311
Unité académique: Cell souches plasticité cellul régénérat tissulaire immuno des maladies inflamm - IRMB
Langue: English
Type de ressource: Journal article
Champs locaux: hal-04959421