De novo missense variants in the E3 ubiquitin ligase adaptor KLHL20 cause a developmental disorder with intellectual disability, epilepsy, and autism spectrum disorder.

Autor:	Sleyp Y; Department of Human Genetics, KU Leuven, Leuven, Belgium., Valenzuela I; Department of Clinical and Molecular Genetics, Vall d'Hebron University Hospital and Medicine Genetics Group, Vall d'Hebron Research Institute, Barcelona, Spain., Accogli A; Medical Genetics Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy., Ballon K; Centre for Developmental Disabilities, University Hospitals Leuven, Leuven, Belgium., Ben-Zeev B; Pediatric Neurology Institute, The Edmond & Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Tel-Hashomer, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel., Berkovic SF; Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia., Broly M; Service de Génétique Médicale, Centre Hospitalier Universitaire (CHU) de Nantes, Nantes, France; Medigenome, Swiss Institute of Genomic Medicine, Geneva, Switzerland., Callaerts P; Department of Human Genetics, KU Leuven, Leuven, Belgium., Caylor RC; Greenwood Genetic Center, Greenwood, SC., Charles P; Salpêtrière Hospital Genetic Department and Reference Center for Rare Intellectual Disabilities, APHP, Paris, France., Chatron N; Department of Medical Genetics, Hospices Civils de Lyon and NeuroMyogene Institute, CNRS UMR 5310 - INSERM U1217, Université Claude Bernard Lyon 1, Lyon, France., Cohen L; Genetic Institute, Barzilai University Medical Center, Ashkelon, Israel; Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheba, Israel., Coppola A; Department of Neuroscience and Reproductive and Odontostomatological Sciences, Federico II University, Naples, Italy., Cordeiro D; Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada., Cuccurullo C; Department of Neuroscience and Reproductive and Odontostomatological Sciences, Federico II University, Naples, Italy., Cuscó I; Department of Clinical and Molecular Genetics, Vall d'Hebron University Hospital and Medicine Genetics Group, Vall d'Hebron Research Institute, Barcelona, Spain., Janette diMonda; Department of Human Genetics, Emory Clinic, Emory Healthcare, Atlanta, GA., Duran-Romaña R; Switch Laboratory, VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium; Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium., Ekhilevitch N; Genetics Institute, Rambam Health Care Campus, Haifa, Israel., Fernández-Alvarez P; Department of Clinical and Molecular Genetics, Vall d'Hebron University Hospital and Medicine Genetics Group, Vall d'Hebron Research Institute, Barcelona, Spain., Gordon CT; Laboratory of Embryology and Genetics of Human Malformations, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Imagine, Université de Paris, Paris, France., Isidor B; Service de Génétique Médicale, Centre Hospitalier Universitaire (CHU) de Nantes, Nantes, France., Keren B; Département de Génétique, AP-HP.Sorbonne Université, Hôpital Pitié-Salpêtrière, Paris, France., Lesca G; Department of Medical Genetics, Hospices Civils de Lyon and NeuroMyogene Institute, CNRS UMR 5310 - INSERM U1217, Université Claude Bernard Lyon 1, Lyon, France., Maljaars J; Parenting and Special Education Research Unit, KU Leuven, Leuven, Belgium., Mercimek-Andrews S; Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Medical Genetics, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada., Morrow MM; GeneDx, Inc, Gaithersburg, MD., Muir AM; Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA., Rousseau F; Switch Laboratory, VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium; Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium., Salpietro V; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy; Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy., Scheffer IE; Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia; Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Victoria, Australia; Florey and Murdoch Children's Research Institutes, Melbourne, Victoria, Australia., Schnur RE; GeneDx, Inc, Gaithersburg, MD., Schymkowitz J; Switch Laboratory, VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium; Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium., Souche E; Center for Human Genetics, University Hospitals Leuven, Leuven, Belgium., Steyaert J; Center for Developmental Psychiatry, KU Leuven, Leuven, Belgium., Stolerman ES; Greenwood Genetic Center, Greenwood, SC., Vengoechea J; Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA., Ville D; Pediatric Neurology Department, Lyon University Hospital, Lyon, France., Washington C; Greenwood Genetic Center, Greenwood, SC., Weiss K; Genetics Institute, Rambam Health Care Campus, Haifa, Israel; The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel., Zaid R; Genetics Institute, Rambam Health Care Campus, Haifa, Israel., Sadleir LG; Department of Paediatrics and Child Health, University of Otago, Wellington, New Zealand., Mefford HC; Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA; Center for Pediatric Neurological Disease Research, St. Jude Children's Research Hospital, Memphis, TN., Peeters H; Department of Human Genetics, KU Leuven, Leuven, Belgium; Center for Human Genetics, University Hospitals Leuven, Leuven, Belgium. Electronic address: hilde.peeters@uzleuven.be.
Jazyk:	angličtina
Zdroj:	Genetics in medicine : official journal of the American College of Medical Genetics [Genet Med] 2022 Dec; Vol. 24 (12), pp. 2464-2474. Date of Electronic Publication: 2022 Oct 11.
DOI:	10.1016/j.gim.2022.08.020
Abstrakt:	Purpose: KLHL20 is part of a CUL3-RING E3 ubiquitin ligase involved in protein ubiquitination. KLHL20 functions as the substrate adaptor that recognizes substrates and mediates the transfer of ubiquitin to the substrates. Although KLHL20 regulates neurite outgrowth and synaptic development in animal models, a role in human neurodevelopment has not yet been described. We report on a neurodevelopmental disorder caused by de novo missense variants in KLHL20. Methods: Patients were ascertained by the investigators through Matchmaker Exchange. Phenotyping of patients with de novo missense variants in KLHL20 was performed. Results: We studied 14 patients with de novo missense variants in KLHL20, delineating a genetic syndrome with patients having mild to severe intellectual disability, febrile seizures or epilepsy, autism spectrum disorder, hyperactivity, and subtle dysmorphic facial features. We observed a recurrent de novo missense variant in 11 patients (NM_014458.4:c.1069G>A p.[Gly357Arg]). The recurrent missense and the 3 other missense variants all clustered in the Kelch-type β-propeller domain of the KLHL20 protein, which shapes the substrate binding surface. Conclusion: Our findings implicate KLHL20 in a neurodevelopmental disorder characterized by intellectual disability, febrile seizures or epilepsy, autism spectrum disorder, and hyperactivity. Competing Interests: Conflict of Interest M.M.M. and R.E.S. are employees of GeneDx, Inc. All other authors declare no conflict interest. (Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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