De novo missense variants in the E3 ubiquitin ligase adaptor KLHL20 cause a developmental disorder with intellectual disability,epilepsy, and autism spectrum disorder |
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| Affiliation: | 1. Department of Human Genetics, KU Leuven, Leuven, Belgium;2. Department of Clinical and Molecular Genetics, Vall d’Hebron University Hospital and Medicine Genetics Group, Vall d’Hebron Research Institute, Barcelona, Spain;3. Medical Genetics Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy;4. Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy;5. Centre for Developmental Disabilities, University Hospitals Leuven, Leuven, Belgium;6. Pediatric Neurology Institute, The Edmond & Lily Safra Children’s Hospital, Sheba Medical Center, Ramat Gan, Tel-Hashomer, Israel;7. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel;8. Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia;9. Service de Génétique Médicale, Centre Hospitalier Universitaire (CHU) de Nantes, Nantes, France;10. Medigenome, Swiss Institute of Genomic Medicine, Geneva, Switzerland;11. Greenwood Genetic Center, Greenwood, SC;12. Salpêtrière Hospital Genetic Department and Reference Center for Rare Intellectual Disabilities, APHP, Paris, France;13. Department of Medical Genetics, Hospices Civils de Lyon and NeuroMyogene Institute, CNRS UMR 5310 - INSERM U1217, Université Claude Bernard Lyon 1, Lyon, France;14. Genetic Institute, Barzilai University Medical Center, Ashkelon, Israel;15. Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheba, Israel;16. Department of Neuroscience and Reproductive and Odontostomatological Sciences, Federico II University, Naples, Italy;17. Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada;18. Department of Human Genetics, Emory Clinic, Emory Healthcare, Atlanta, GA;19. Switch Laboratory, VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium;20. Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium;21. Genetics Institute, Rambam Health Care Campus, Haifa, Israel;22. 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;23. Département de Génétique, AP-HP.Sorbonne Université, Hôpital Pitié-Salpêtrière, Paris, France;24. Parenting and Special Education Research Unit, KU Leuven, Leuven, Belgium;25. Department of Medical Genetics, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada;26. GeneDx, Inc, Gaithersburg, MD;27. Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA;28. Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy;29. Department of Paediatrics, University of Melbourne, Royal Children''s Hospital, Victoria, Australia;30. Florey and Murdoch Children’s Research Institutes, Melbourne, Victoria, Australia;31. Center for Human Genetics, University Hospitals Leuven, Leuven, Belgium;32. Center for Developmental Psychiatry, KU Leuven, Leuven, Belgium;33. Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA;34. Pediatric Neurology Department, Lyon University Hospital, Lyon, France;35. The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel;36. Department of Paediatrics and Child Health, University of Otago, Wellington, New Zealand;37. Center for Pediatric Neurological Disease Research, St. Jude Children’s Research Hospital, Memphis, TN;1. Department of Neurology, School of Medicine, University of Sao Paulo, Sao Paulo, Brazil;2. Molecular Neurogenomics Group, VIB-UAntwerp Center for Molecular Neurology, University of Antwerp, Antwerp, Belgium;3. Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium;4. Medical Department, Mendelics Genomic Analysis, Sao Paulo, Brazil;1. Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan;2. Department of Pediatrics, Yokohama City University Graduate School of Medicine, Yokohama, Japan;3. Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan;4. Department of Pediatric Neurology, Miyagi Children’s Hospital, Sendai, Japan;5. Department of Pediatrics, Tohoku University Hospital, Tohoku University, Sendai, Japan;6. Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan;7. Department of Neurology, Kanagawa Children’s Medical Center, Yokohama, Japan;8. Division of Medical Genetics, Kanagawa Children’s Medical Center, Yokohama, Japan;9. Department of Pediatrics, Jichi Medical University, Tochigi, Japan;10. Department of Child Neurology, NHO Nishiniigata Chuo Hospital, Niigata, Japan;11. Department of Medical Genetics, Osaka Women’s and Children’s Hospital, Izumi, Japan;12. Department of Neuropediatrics, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan;13. Department of Pediatric Neurology, Children’s Medical Center, Osaka City General Hospital, Osaka, Japan;14. Department of Pediatrics, Tokyo Metropolitan Higashiyamato Medical Center for Developmental/Multiple Disabilities, Tokyo, Japan;15. Department of Pediatric Neurology, Seirei-Mikatahara General Hospital, Hamamatsu, Japan;16. Department of Pediatrics, Showa University School of Medicine, Tokyo, Japan;17. Division of Neurology, Nagano Children’s Hospital, Azumino, Nagano, Japan;18. Division of Rehabilitation, Nagano Children’s Hospital, Azumino, Nagano, Japan;19. Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan;20. Department of Pediatrics, Tsuchiura Kyodo General Hospital, Ibaraki, Japan;21. Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan;22. Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan;23. Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Japan;24. Department of Pediatrics, Fukuoka University Faculty of Medicine, Fukuoka, Japan;25. Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan;26. Department of Pediatrics, School of Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan;27. Department of Pediatrics, Graduate School of Medicine, Gunma University, Gunma, Japan;28. Department of Pediatric Neurology, Aichi Developmental Disability Center Central Hospital, Aichi, Japan;29. Department of Pediatrics, School of Medicine, Tokyo Women’s Medical University, Tokyo, Japan;30. Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan;31. Department of Pediatrics, School of Medicine, Iwate Medical University, Iwate, Japan;32. Department of Pediatrics, Matsudo City General Hospital, Matsudo, Japan;33. Department of Pediatrics, Nara Medical University, Nara, Japan;34. Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan;35. Department of Neonatology, Mie Chuo Medical Center, National Hospital Organization, Tsu, Japan;36. Department of Pediatrics, Mie University School of Medicine, Mie, Japan;37. Department of Pediatric Genetics, S.B.Ü. Dr. Behçet Uz Children’s Education and Research Hospital, Izmir, Turkey;38. Department of Pediatric Genetics, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey;39. Unidade de Genética Clínica, Instituto da Criança do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil;40. Department of Genetics, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia;41. Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan;42. Department of Rare Disease Genomics, Yokohama City University Hospital, Yokohama, Japan;43. RIKEN Center for Advanced Intelligence Project, Tokyo, Japan;44. Department of Clinical Genetics, Yokohama City University Hospital, Yokohama, Japan;45. Department of Human Genetics, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan;1. Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada;2. Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario, Canada;3. Department of Medical Genetics, University of Calgary, Calgary, Alberta, Canada;4. Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands;5. Department of Clinical Genetics, Liverpool Hospital, Sydney, New South Wales, Australia;6. School of Women’s and Children’s Health, University of New South Wales, Sydney, New South Wales, Australia;7. German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstaedter Landstraße, Neuherberg, Germany;8. Chair of Experimental Genetics, TUM School of Life Sciences, Technische Universität München, Freising, Germany;9. German Center for Diabetes Research (DZD), Ingolstaedter Landstraße, Neuherberg, Germany;10. Division of Neurology, The Hospital for Sick Children, Toronto, Ontario, Canada;11. Departments of Paediatrics and Biochemistry, University of Toronto, Toronto, Ontario, Canada;1. Pediatric Neurology and Metabolic Medicine, Center for Pediatrics and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany;2. Center for Rare Disorders, Heidelberg University Hospital, Heidelberg, Germany;3. Center for Virtual Patients, Heidelberg Faculty of Medicine, Heidelberg, Germany;4. SphinCS - Institute for Clinical Research in Lysosomal Storage Disorders, Hochheim, Germany;5. Hand in Hand against Tay-Sachs and Sandhoff disease in Germany, Höchberg, Germany;6. Institute of Human Genetics, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany;1. Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN;2. Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN;1. Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetric and Gynecologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China;2. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX;3. Medical Scientist Training Program, Baylor College of Medicine, Houston, TX;4. Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China;5. Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China;6. Department of Gynecology and Obstetrics, Research Centre for Women''s Health, Tübingen University Hospital, Tübingen, Germany;7. Department of Orthopedic Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China;8. Department of Obstetrics and Gynecology, The 3rd Affiliated Hospital of Shenzhen University, Luohu Hospital, Shenzhen, Guangdong, China;9. Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland;10. Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX;11. Key Laboratory of Big Data for Spinal Deformities, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China;12. Department of Cardiology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China;13. Medical Research Center, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China;14. Center for Adolescent Medicine and UNESCO Chair in Adolescent Health Care, First Department of Pediatrics, School of Medicine, National and Kapodistrian University of Athens, Aghia Sophia Children''s Hospital, Athens, Greece;15. Division of Pediatric-Adolescent Gynecology and Reconstructive Surgery, 2nd Department of Obstetrics and Gynecology, School of Medicine, National and Kapodistrian University of Athens, Aretaieion Hospital, Athens, Greece;16. Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of Sao Paulo, Sao Paulo, Brazil;17. Department of Pediatrics, Baylor College of Medicine, Houston, TX;18. Department of Obstetrics and Gynecology, Texas Children''s Hospital and Baylor College of Medicine, Houston, TX;19. Texas Children''s Hospital, Houston, TX;20. Institute for Bioinnovation, Biomedical Sciences Research Center Alexander Fleming, Vari, Athens, Greece;21. Baylor Genetics, Houston, TX;22. Institute of Genetics and Genomics in Geneva, University of Geneva, Geneva, Switzerland |
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| Abstract: | PurposeKLHL20 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.MethodsPatients were ascertained by the investigators through Matchmaker Exchange. Phenotyping of patients with de novo missense variants in KLHL20 was performed.ResultsWe 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.ConclusionOur findings implicate KLHL20 in a neurodevelopmental disorder characterized by intellectual disability, febrile seizures or epilepsy, autism spectrum disorder, and hyperactivity. |
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| Keywords: | KLHL20 E3 ubiquitin ligase Autism Epilepsy Intellectual disability |
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