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

Autor:	Kalm T; Institute for Cellular and Integrative Physiology, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany., Schob C; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany., Völler H; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany., Gardeitchik T; Department of Human Genetics, Radboud University Medical Center, Nijmegen 6525 GA, the Netherlands., Gilissen C; Department of Human Genetics, Radboud University Medical Center, Nijmegen 6525 GA, the Netherlands., Pfundt R; Department of Human Genetics, Radboud University Medical Center, Nijmegen 6525 GA, the Netherlands., Klöckner C; Institute of Human Genetics, University of Leipzig Medical Center, 04103 Leipzig, Germany., Platzer K; Institute of Human Genetics, University of Leipzig Medical Center, 04103 Leipzig, Germany., Klabunde-Cherwon A; Division of Pediatric Epileptology, Centre for Paediatric and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany., Ries M; Division of Pediatric Epileptology, Centre for Paediatric and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany., Syrbe S; Division of Pediatric Epileptology, Centre for Paediatric and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany., Beccaria F; Epilepsy Center, Department of Child Neuropsychiatry, Territorial Social-Health Agency, 46100 Mantova, Italy., Madia F; Medical Genetics Unit, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy., Scala M; Medical Genetics Unit, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, 16145 Genoa, Italy., Zara F; Medical Genetics Unit, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, 16145 Genoa, Italy., Hofstede F; Department of General Pediatrics, Wilhelmina Children's Hospital, University Medical Centre Utrecht, Utrecht, the Netherlands., Simon MEH; Department of Clinical Genetics, University Medical Center Utrecht, Utrecht 3584 EA, the Netherlands., van Jaarsveld RH; Department of Clinical Genetics, University Medical Center Utrecht, Utrecht 3584 EA, the Netherlands., Oegema R; Department of Clinical Genetics, University Medical Center Utrecht, Utrecht 3584 EA, the Netherlands., van Gassen KLI; Department of Clinical Genetics, University Medical Center Utrecht, Utrecht 3584 EA, the Netherlands., Holwerda SJB; Department of Clinical Genetics, University Medical Center Utrecht, Utrecht 3584 EA, the Netherlands., Barakat TS; Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam 3000 CA, the Netherlands; ENCORE Expertise Center for Neurodevelopmental Disorders, Erasmus MC University Medical Center, Rotterdam 3000 CA, the Netherlands; Discovery Unit, Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam 3000 CA, the Netherlands., Bouman A; Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam 3000 CA, the Netherlands., van Slegtenhorst M; Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam 3000 CA, the Netherlands., Álvarez S; Genomics and Medicine, NIMGenetics, 28108 Madrid, Spain., Fernández-Jaén A; Pediatric Neurology Department, Quironsalud University Hospital Madrid, School of Medicine, European University of Madrid, 28224 Madrid, Spain., Porta J; Genomics, Genologica Medica, 29016 Málaga, Spain., Accogli A; Division of Medical Genetics, Department of Specialized Medicine, Montreal Children's Hospital, McGill University Health Centre, QC H4A 3J1 Montreal, Canada; Department of Human Genetics, McGill University, QC H4A 3J1 Montreal, Canada., Mancardi MM; Child Neuropsychiatry Unit, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy., Striano P; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, 16145 Genoa, Italy; Pediatric Neurology and Neuromuscular Diseases Unit, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy., Iacomino M; Medical Genetics Unit, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy., Chae JH; Department of Pediatrics, Seoul National University College of Medicine, Seoul 110-744, Republic of Korea; Department of Genomic Medicine, Rare Disease Center, Seoul National University Hospital, Seoul 03080, Republic of Korea., Jang S; Department of Pediatrics, Seoul National University College of Medicine, Seoul 110-744, Republic of Korea., Kim SY; Department of Genomic Medicine, Rare Disease Center, Seoul National University Hospital, Seoul 03080, Republic of Korea., Chitayat D; The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto ON M5G 1E2 Toronto, Canada; Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for SickKids, University of Toronto, M5G 1X8 Toronto, Canada., Mercimek-Andrews S; Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for SickKids, University of Toronto, M5G 1X8 Toronto, Canada; Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, AB T6G 2H7 Edmonton, Canada., Depienne C; Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany., Kampmeier A; Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany., Kuechler A; Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany., Surowy H; Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany., Bertini ES; Neuromuscular Disorders, Bambino Gesù Children's Hospital, IRCCS, 00146 Rome, Italy., Radio FC; Molecular Genetics and Functional Genomics, Bambino Gesù Children's Hospital, IRCCS, 00146 Rome, Italy., Mancini C; Molecular Genetics and Functional Genomics, Bambino Gesù Children's Hospital, IRCCS, 00146 Rome, Italy., Pizzi S; Molecular Genetics and Functional Genomics, Bambino Gesù Children's Hospital, IRCCS, 00146 Rome, Italy., Tartaglia M; Molecular Genetics and Functional Genomics, Bambino Gesù Children's Hospital, IRCCS, 00146 Rome, Italy., Gauthier L; Department of Molecular Genetics and Cytogenomics, Rare and Autoinflammatory Diseases Unit, University Hospital of Montpellier, 34295 Montpellier, France., Genevieve D; Montpellier University, Inserm U1183, Montpellier, France; Department of Clinical Genetics, University Hospital of Montpellier, 34295 Montpellier, France., Tharreau M; Department of Molecular Genetics and Cytogenomics, Rare and Autoinflammatory Diseases Unit, University Hospital of Montpellier, 34295 Montpellier, France., Azoulay N; The Genetic Institute of Maccabi Health Services, Rehovot 7610000, Israel; Raphael Recanati Genetics Institute, Beilinson Hospital, Rabin Medical Center, Petach Tikva 49100, Israel., Zaks-Hoffer G; Raphael Recanati Genetics Institute, Beilinson Hospital, Rabin Medical Center, Petach Tikva 49100, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel., Gilad NK; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; Pediatric Genetics Unit, Schneider Children's Medical Center of Israel, Petah Tikvah 4920235, Israel., Orenstein N; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; Pediatric Genetics Unit, Schneider Children's Medical Center of Israel, Petah Tikvah 4920235, Israel., Bernard G; Division of Medical Genetics, Department of Specialized Medicine, Montreal Children's Hospital, McGill University Health Centre, QC H4A 3J1 Montreal, Canada; Departments of Neurology and Neurosurgery, Pediatrics and Human Genetics, McGill University, Montreal, Canada; Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montreal, Canada., Thiffault I; Genomic Medicine Center, Department of Pediatrics, Children's Mercy Kansas City, Kansas City, MO, USA; UKMC School of Medicine, University of Missouri Kansas City, Kansas City, MO, USA; Department of Pathology and Laboratory Medicine, Children's Mercy Kansas City, Kansas City, MO, USA., Denecke J; Department of Pediatrics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany., Herget T; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany., Kortüm F; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany., Kubisch C; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany., Bähring R; Institute for Cellular and Integrative Physiology, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany. Electronic address: r.baehring@uke.uni-hamburg.de., Kindler S; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany. Electronic address: kindler@uke.de.
Jazyk:	angličtina
Zdroj:	American journal of human genetics [Am J Hum Genet] 2024 Jun 06; Vol. 111 (6), pp. 1206-1221. Date of Electronic Publication: 2024 May 20.
DOI:	10.1016/j.ajhg.2024.04.019
Abstrakt:	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. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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