Genotype-phenotype correlations in RHOBTB2-associated neurodevelopmental disorders |
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| Affiliation: | 1. Department of Human Genetics, Inselspital Bern, University of Bern, Bern, Switzerland;2. Department for Biomedical Research (DBMR), University of Bern, Bern, Switzerland;3. Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom;4. Department of Neurology, Thomas Jefferson University, Philadelphia, PA;5. Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands;6. Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;7. Department of Genetics, La Pitié-Salpêtrière Hospital, APHP, Sorbonne University, Paris, France;8. Division of Medical Genetics, Department of Pediatrics, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ;9. The Neurology Department at Sheba Medical Center, Ramat Gan, Israel;10. Brain Development Research Program, Department of Neurology, University of California San Francisco, San Francisco, CA;11. Department of Pediatric Neurology, Indira Gandhi Institute of Child Health, Bangalore, Karnataka, India;12. Pediatric Movement Disorders Program, Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children’s Hospital, Phoenix, AZ;13. Departments of Child Health, Neurology, and Cellular & Molecular Medicine, and Program in Genetics, University of Arizona College of Medicine-Phoenix, Phoenix, AZ;14. Division of Pediatric Neurology, College of Medicine, King Saud University, Riyadh, Saudi Arabia;15. Department of Pediatrics, College of Medicine, Almughtaribeen University, Khartoum, Sudan;16. Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, Essen, Germany;17. Clinical Genetics, Stanford Children''s Health, San Francisco, CA;18. Department of Clinical Genetics, PEDEGO Research Unit and Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland;19. Anschutz Medical Campus Department of Pediatrics and Neurology, University of Colorado School of Medicine, Aurora, CO;20. Section of Genetics, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO;21. Division of Genetics, Loma Linda University Health, San Bernardino, CA;22. Department of pediatrics, MediClubGeorgia Medical Center, Tbilisi, Georgia;23. Victorian Clinical Genetics Services, Murdoch Children’s Research Institute, Melbourne, VIC, Australia;24. Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia;25. Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, WA;26. Department of Pediatrics, University of Washington, Seattle, WA;27. Brotman Baty Institute for Precision Medicine, Seattle, WA;28. Child Neurology Consultants of Austin, Austin, TX;29. Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany;30. Department of Pediatric Neurology and Developmental Medicine, Children’s Hospital, University Hospital of Tuebingen, Tuebingen, Germany;31. Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany;32. Department of Pediatrics, University of Leipzig Medical Center, Leipzig, Germany;33. Division of Medical Genetics, Massachusetts General Hospital, Boston, MA;34. Pediatric Neurology Department, American Center for Psychiatry and Neurology, Abu Dhabi, United Arab Emirates;35. Pediatric Neurology department, Haykel Hospital, El Koura, Lebanon;36. Genetics Unit, Medical Sciences Research Laboratory, Faculty of Medicine and Pharmacy, University Mohammed Premier, Oujda, Morocco;37. BRO Biobank, Faculty of Medicine and Pharmacy, University Mohammed Premier, Oujda, Morocco;38. Genetics and Immuno-Cell Therapy Team, Mohammed First University, Oujda, Morocco;39. Department of Neonatology, Mohammed VI University Hospital, Faculty of Medicine and Pharmacy, University Mohammed Premier, Oujda, Morocco;40. Genetic and Precision Medicine Department, King Abdullah Specialized Children Hospital, King Abdulaziz Medical City, King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia;41. Pediatric Neurology Section-Pediatric Department, King Faisal Specialist Hospital & Research Center (Gen. Org) - Jeddah Branch, Riyadh, Saudi Arabia;42. Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia;43. Department of Pediatric Neurology, Children’s Hospital and Institute of Child Health, Lahore, Pakistan;44. Department of Pediatrics, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran;45. Molecular and Clinical Sciences Institute, St. George’s, University of London, Cranmer Terrace, London, United Kingdom;46. Department of Pediatrics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran;47. Department of Pediatric Neurology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran;48. Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany;1. Frazer Institute, The University of Queensland, Dermatology Research Centre, Brisbane, QLD, Australia;2. Clinical Translational and Engagement Platform, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia;3. School of Clinical Medicine, UNSW Medicine & Health, St Vincent’s Healthcare Clinical Campus, Faculty of Medicine and Health, UNSW Sydney, Kensington, NSW, Australia;4. Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre and the Royal Melbourne Hospital, Melbourne, VIC, Australia;5. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia;6. Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia;7. Hereditary Cancer Centre, Prince of Wales Hospital, Randwick, NSW, Australia;8. School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Kensington, NSW, Australia;1. Department of Pathology, University of Utah, Salt Lake City, UT;2. Department of Genetics, Stanford University, Stanford, CA;3. Department of Pediatrics, Division of Medical Genetics, Stanford University, Stanford, CA;4. Department of Genetics and Division of Medical Genetics, Stanford University, Stanford, CA;5. Department of Internal Medicine, University of Utah, Salt Lake City, UT;6. University of Utah School of Medicine, Salt Lake City, Utah;7. Division of Cardiovascular Medicine, Department of Medicine, HHT Center, University of Utah, Salt Lake City, UT;1. Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC;2. Mitochondrial Medicine Frontier Program, Division of Human Genetics, Children''s Hospital of Philadelphia, Philadelphia, PA;3. Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA;4. Division of Neuroradiology, Department of Radiology, Duke University Medical Center, Durham, NC;5. Synlogic Therapeutics, Boston, MA;6. Department of Pediatrics, Duke University School of Medicine, Durham, NC;7. Department of Immunology, Duke University Medical Center, Durham, NC;8. Center for Human Disease Modeling, Duke University Medical Center, Durham, NC;9. Duke Precision Medicine Program, Department of Medicine, Division of General Internal Medicine, Duke University Medical Center, Durham, NC;10. Pediatric Stem Cell Transplant and Cellular Therapy, Department of Pediatrics, University of Virginia, Charlottesville, VA;11. Stanley Manne Children’s Research Institute, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL;12. Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada;13. Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada;14. Department of Ophthalmology, Duke University Medical Center, Durham, NC;15. Division of Neurology, Department of Pediatrics, Duke University Medical Center, Durham, NC;16. Department of Neurology, University of North Carolina at Chapel Hill, NC;17. Departments of Pediatrics and Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL;1. HudsonAlpha Institute for Biotechnology, Huntsville, AL;2. Washington University School of Medicine, St. Louis, MO;3. Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY;4. Division of Pediatric Genetic Medicine, Department of Pediatrics, Children’s Hospital at Montefiore/Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY;5. University of Alabama in Birmingham, Birmingham, AL;6. HudsonAlpha Clinical Services Lab, Huntsville, AL;7. University of Mississippi Medical Center, Jackson, MS;8. Department of Neurology, University of Alabama at Birmingham, Birmingham, AL;9. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY;10. Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY;1. Genetics Section, Molecular and Clinical Sciences Research Institute, St. George’s, University of London, London, United Kingdom;2. Aging & Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK;3. Innovative Medical Research Centre, Faculty of Medicine, Islamic Azad University-Mashhad Branch, Mashhad, Iran;4. Division of Medical Genetics, Department of Specialized Medicine, McGill University Health Center, Department of Human Genetics, McGill University, Montreal, Canada;5. Division of Inborn Errors of Metabolism, Department of Pediatrics, Izmir Katip Çelebi University Faculty of Medicine, Izmir, Turkey;6. Mitochondrial Medicine Frontier Program, Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA;7. Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA;8. Department of Pediatrics, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran;9. Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran;10. Department of Medical Genetics, Next Generation Genetic Polyclinic, Mashhad Iran;11. Children’s Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran;12. Division of Medical Genetics, Department of Specialized Medicine, McGill University Health Centre, Montreal, Canada;13. GeneDx, Gaithersburg, MD;14. Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX;15. Department of Neuromuscular Disorders, UCL Institute of Neurology, University College London, London, United Kingdom;16. Division of Child Neurology, Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland;17. Mitochondrial Research Group, UCL Great Ormond Street Institute of Child Health, and Metabolic Unit, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom;1. CHU Sainte-Justine Research Center, Montréal, QC, Canada;2. Service de Génétique Médicale, Hôpital Purpan CHU Toulouse, Toulouse, France;3. Centre de Référence des Affections Rares en Génétique Ophtalmologique CARGO, CHU Toulouse, Toulouse, France;4. Faculty of Health and Life Sciences, Oxford Brookes University, Oxford, United Kingdom;5. West Midlands Regional Genetics Service, Birmingham Women’s and Children’s NHS Foundation Trust and Birmingham Health Partners, Birmingham, United Kingdom;6. Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute for Medical Genetics and Human Genetics, Berlin, Germany;7. Pediatric Genomic Discovery Program, Department of Pediatrics, Yale University School of Medicine, New Haven, CT;8. Department of Pediatrics, University of Rochester Medical Center, Rochester, NY;9. Department of Medical Genetics, Alberta Children’s Hospital, Calgary, AB, Canada;10. Department of Human Genetics, Amsterdam UMC, Amsterdam, The Netherlands;11. Department of Pediatric Neurology, Amsterdam UMC, location Vrije Universiteit, Amsterdam, The Netherlands;12. Division of Medical Genetics, Children''s Hospital Los Angeles, Los Angeles, CA;13. Service de Génétique médicale, CHU de Poitiers, Poitiers, France;14. Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden;15. Department of Clinical genetics, Karolinska University Hospital, Stockholm, Sweden;16. Department of Pediatric Neurology, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany;17. Department of Pediatrics, Université de Montréal, Montréal, QC, Canada;18. UF de fœtopathologie, Hôpital Robert Debré, Paris, France;19. Service de médecine génomique des maladies rares, Hôpital Universitaire Necker-Enfants malade, Paris, France;20. Centre Hospitalier d’Angoulême, Angoulême, France;21. Exploration de la Vision et Neuro-Ophtalmologie, Hôpital Roger-Salengro, CHU de Lille, Lille, France;22. Service d’ophtalmologie, Hôpital Claude Huriez, CHU de Lille, Lille, France;23. Medical Genetics, CHU La Reunion, Reunion Island, France;24. Unité de Génétique Clinique, Hôpital Robert Debré, Paris, France;25. Servicio de Pediatría, Hospital de Sagunto, Valencia, Spain;26. Medical Genetics Unit, Sistemas Genómicos, Paterna, Spain;27. Department of Neurology, Rosamund Stone Zander Translational Neuroscience Center, Boston Children’s Hospital, Boston, MA;28. Clinique de Génétique “Guy Fontaine,” Hôpital Jeanne de Flandre, Lille, France;29. Division of Medical Genetics and Genomics, Stead Family Department of Pediatrics, University of Iowa Hospitals and Clinics, Iowa City, IA;30. Division of Child Neurology, Stead Family Department of Pediatrics, Department of Neurology, UI Carver College of Medicine, Iowa City, IA;31. Department of Pediatrics and Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX;32. Texas Children’s Hospital, Houston, TX;33. Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX;34. Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX;35. Université Montpellier, INSERM U1183, Génétique clinique, CHU de Montpellier, Montpellier, France;36. Service de Génétique, Hospices Civils de Lyon, Lyon, France;37. Institut Neuromyogène, CNRS UMR 5310 - INSERM U1217, Université Claude Bernard Lyon 1, Lyon, France;38. Division of Neurology, Department of Pediatrics, McGill University Health Centre, Montreal, QC, Canada;39. Department of Pediatrics, University of Minnesota, Minneapolis, MN;40. Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom;41. Children’s & Adolescent Services, Royal Surrey County Hospital, Guildford, Surrey, United Kingdom;42. St George’s University Hospitals NHS Foundation Trust, London, United Kingdom;43. Berkeley Center for Structural Biology, Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA;44. Department of Obstetrics & Gynecology, Université de Montréal, Montréal, QC, Canada;45. Department of Biochemistry and Molecular Medecine, Université de Montréal, Montréal, QC, Canada;46. Department of Neurosciences, Université de Montréal, Montréal, QC, Canada |
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| Abstract: | PurposeMissense variants clustering in the BTB domain region of RHOBTB2 cause a developmental and epileptic encephalopathy with early-onset seizures and severe intellectual disability.MethodsBy international collaboration, we assembled individuals with pathogenic RHOBTB2 variants and a variable spectrum of neurodevelopmental disorders. By western blotting, we investigated the consequences of missense variants in vitro.ResultsIn accordance with previous observations, de novo heterozygous missense variants in the BTB domain region led to a severe developmental and epileptic encephalopathy in 16 individuals. Now, we also identified de novo missense variants in the GTPase domain in 6 individuals with apparently more variable neurodevelopmental phenotypes with or without epilepsy. In contrast to variants in the BTB domain region, variants in the GTPase domain do not impair proteasomal degradation of RHOBTB2 in vitro, indicating different functional consequences. Furthermore, we observed biallelic splice-site and truncating variants in 9 families with variable neurodevelopmental phenotypes, indicating that complete loss of RHOBTB2 is pathogenic as well.ConclusionBy identifying genotype-phenotype correlations regarding location and consequences of de novo missense variants in RHOBTB2 and by identifying biallelic truncating variants, we further delineate and expand the molecular and clinical spectrum of RHOBTB2-related phenotypes, including both autosomal dominant and recessive neurodevelopmental disorders. |
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| Keywords: | Developmental and epileptic encephalopathy Intellectual disability Neurodevelopmental disorder RHOBTB2 Seizures |
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