Biallelic loss-of-function variants in RABGAP1 cause a novel neurodevelopmental syndrome |
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| Affiliation: | 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. Hunan Normal University School of Medicine, Changsha, Hunan, China;2. National Engineering and Research Center of Human Stem Cells, Changsha, China;3. Hunan International Scientific and Technological Cooperation Base of Development and Carcinogenesis, Changsha, Hunan, China;4. BGI-Shenzhen, Shenzhen, China;5. Institute of Reproductive and Stem Cell Engineering, NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, School of Basic Medical Science, Central South University, Changsha, Hunan, China;6. Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, Hunan, China;7. BGI Education Center, University of Chinese Academy of Sciences, Shenzhen, China;1. Paris Brain Institute (Institut du Cerveau, ICM), INSERM, CNRS, Assistance Publique-Hôpitaux de Paris (AP-HP), Sorbonne Université, Paris, France;2. Pasteur Institute, Centre National de la Recherche Scientifique UMR 3691, Paris, France;3. Université de Bordeaux, CNRS, EPHE, INCIA, UMR 5287, Bordeaux, France;4. Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands;5. Département de Génétique, AP-HP, GH Pitié-Salpêtrière, Sorbonne Université, Paris, France;6. Sorbonne Université, Inserm, UMS Production et Analyse des données en Sciences de la vie et en Santé, PASS, Plateforme Post-génomique de la Pitié-Salpêtrière, P3S, Paris, France;7. Rare Neurological Diseases Unit, Department of Neurology, Attikon University Hospital, Medical School of the University of Athens, Athens, Greece;8. Institut für Humangenetik, Universitätsklinikum Essen, Essen, Germany;9. Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands;1. Department of Pediatrics, Stanford University School of Medicine, Stanford, CA;2. Division of Medical Genetics, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA;3. Division of Developmental and Behavioral Pediatrics, Department of Pediatrics, Stanford Medicine, Stanford, CA;1. Social and Behavioral Research Branch, National Human Genome Research Institute, Bethesda, MD;1. Medical Genetics Service, Gaffrée and Guinle University Hospital, Universidade Federal do Estado do Rio de Janeiro, Rio de Janeiro, Brazil;2. D’Or Institute of Research and Education (IDOR), Rio de Janeiro, Brazil;3. Centro de Genética Médica do Rio de Janeiro, Rio de Janeiro, Brazil;4. Birth Defects Epidemiology Laboratory, Oswaldo Cruz Institute, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil;1. Nantes Université, CHU Nantes, Service de Génétique Médicale, Nantes, France;2. Nantes Université, CHU Nantes, CNRS, INSERM, l’institut du thorax, Nantes, France;3. Hatherly Laboratories, The Institute of Biomedical and Clinical Sciences, College of Medicine and Health, University of Exeter, Exeter, United Kingdom;4. Department of Neurosurgery, Yale School of Medicine, Yale University, New Haven, CT;5. State Key Laboratory of Bio-Organic and Natural Products Chemistry, Research Center of Chemical Kinomics, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China;6. Unidad de Genética, Hospital Universitario y Politécnico La Fe, Valencia, Spain;7. Department of Genetics, Yale School of Medicine, Yale University, New Haven, CT;8. Département de Biochimie et Génétique, Centre Hospitalier Universitaire Angers, Angers, France;9. UMR CNRS 6214, INSERM 1083, Université d’Angers, Angers, France;10. Departments of Human Genetics and Pediatrics, School of Medicine, Emory University, Atlanta, GA;11. Greenwood Genetic Center, Greenwood, SC;12. GeneDx, Gaithersburg, MD;13. Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Biomedical Campus Cambridge, Cambridge, United Kingdom;14. Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA;15. Medigenome, Swiss Institute of Genomic Medicine, Geneva, Switzerland;16. Centre for Trials Research, Cardiff University, Cardiff, United Kingdom;17. Centre de Génétique Humaine, CHU de Besançon, Université de Bourgogne Franche-Comté, Besançon, France;18. Department of Genetics, Centre de Référence Déficiences Intellectuelles de Causes Rares, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France;19. Department of Clinical Genetics, Genetics and Personalized Medicine Clinic, Tartu University Hospital, Tartu, Estonia;20. Department of Clinical Genetics, Institute of Clinical Medicine, Faculty of Medicine, University of Tartu, Tartu, Estonia;21. Department of Radiology, Tartu University Hospital, Tartu, Estonia;22. Groupe de Recherche Clinique, Déficience Intellectuelle et Autisme, Sorbonne University, Paris, France;23. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA;24. Genomic Informatics Group, University of Southampton, Southampton, United Kingdom;25. Developmental Brain Disorders laboratory, INSERM UMR 1163, Imagine Institute, University of Paris, Paris, France;26. Department of Genetics, Centre de Référence Déficiences Intellectuelles de Causes Rares, Necker Enfants Malades Hospital, APHP, Paris, France;27. Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, the Netherlands;28. Departments of Pediatrics and Medicine, Columbia University Irving Medical Center, Columbia University New York, NY;29. Division of Clinical Genetics, Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons and New York-Presbyterian Morgan Stanley Children’s Hospital, New York, NY;30. Division of Pediatric Neurology, Department of Pediatrics, Centre Hospitalier de Luxembourg, Luxembourg City, Luxembourg;31. Neurogenetics Research Group, Reproduction and Genetics, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Laarbeeklaan, Brussels, Belgium;32. Department of Radiology and Imaging Sciences, School of Medicine, Emory University, Atlanta, GA;33. Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX;34. Service de Génétique, CHU Poitiers, Poitiers, France;35. Génétique Médicale, CHRU Brest, Brest, France;36. Service de Génétique Clinique, ERN ITHACA, CHU Rennes, Rennes, France;37. Institut de Génétique et Développement de Rennes, IGDR UMR 6290 CNRS, INSERM, IGDR Univ Rennes, Rennes, France;38. Unité de Génétique Médicale, Centre Hospitalier Régional Universitaire de Tours, France;39. Unité Mixte de Recherche 1253, iBrain, Université de Tours, Institut National de la Santé et de la Recherche Médicale, Tours, France;40. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX;41. Department of Pharmaceutical and Biological Chemistry, UCL School of Pharmacy, University College London, London, United Kingdom;42. Centre for Advanced Research Computing, University College London, London, United Kingdom;43. Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland;44. iGE3, Institute of Genetics and Genomics of Geneva, University of Geneva, Geneva, Switzerland;45. Department of Cellular and Molecular Physiology, Yale School of Medicine, Yale University, New Haven, CT;46. NIH-Yale Centers for Mendelian Genomics, Yale School of Medicine, Yale University, New Haven, CT;47. Yale Stem Cell Center, Yale School of Medicine, Yale University, New Haven, CT |
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| Abstract: | PurposeRABGAP1 is a GTPase-activating protein implicated in a variety of cellular and molecular processes, including mitosis, cell migration, vesicular trafficking, and mTOR signaling. There are no known Mendelian diseases caused by variants in RABGAP1.MethodsThrough GeneMatcher, we identified 5 patients from 3 unrelated families with homozygous variants in the RABGAP1 gene found on exome sequencing. We established lymphoblastoid cells lines derived from an affected individual and her parents and performed RNA sequencing and functional studies. Rabgap1 knockout mice were generated and phenotyped.ResultsWe report 5 patients presenting with a common constellation of features, including global developmental delay/intellectual disability, microcephaly, bilateral sensorineural hearing loss, and seizures, as well as overlapping dysmorphic features. Neuroimaging revealed common features, including delayed myelination, white matter volume loss, ventriculomegaly, and thinning of the corpus callosum. Functional analysis of patient cells revealed downregulated mTOR signaling and abnormal localization of early endosomes and lysosomes. Rabgap1 knockout mice exhibited several features in common with the patient cohort, including microcephaly, thinning of the corpus callosum, and ventriculomegaly.ConclusionCollectively, our results provide evidence of a novel neurodevelopmental syndrome caused by biallelic loss-of-function variants in RABGAP1. |
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| Keywords: | Autosomal recessive GTPase-activating protein Neurodevelopmental syndrome Novel Mendelian disorder |
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