Biallelic PRMT7 pathogenic variants are associated with a recognizable syndromic neurodevelopmental disorder with short stature,obesity, and craniofacial and digital abnormalities |
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| Affiliation: | 1. Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom;2. Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust, City Hospital Campus, Nottingham, United Kingdom;3. Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy;4. Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy;5. Genomic Medicine theme, Oxford Biomedical Research Centre, NIHR, Oxford, Oxfordshire, United Kingdom;6. Wellcome Centre for Human Genetics, Oxford University, Oxford, Oxfordshire, United Kingdom;7. Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran;8. Palindrome, Isfahan, Iran;9. Section of Medical Genetics, Children’s Specialist Hospital, King Fahad Medical, City, Riyadh, Saudi Arabia;10. Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands;11. Division of Medical Genetics, Department of Pediatrics, University of California, and Rady Children’s Hospital, San Diego, CA;12. Wessex Clinical Genetics Service, Princess Anne Hospital, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom;13. Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, United Kingdom;14. Medical Genetics Research Center, Shahid Sadoughi University of Medical Science, Yazd, Iran;15. Division of Human Genetics, Warren Alpert Medical School of Brown University, Hasbro Children’s Hospital/Rhode Island Hospital, Providence, RI;16. Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany;17. Institute of Medical Genetics, University of Zurich, Zurich, Switzerland;18. Department of Translational Genomics, Center for Genomics Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia;19. Section of Medical Genetics, Department of Pediatrics, Ochsner Health System and University of Queensland, New Orleans, LA;20. Department of Pediatrics and Molecular and Human Genetics, Baylor College of Medicine, San Antonio, TX;21. Department of Medical Genetics, Kepler University Hospital Med Campus IV, Johannes Kepler University, Linz, Austria;22. Children''s Hospital of Orange County, Orange, CA;23. Genetics Center, Orange, California;24. Department of Neurology, Boston Children’s Hospital, Boston, MA;25. Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA;26. Department of Genetics and Reference Center for Developmental Disorders, Normandie University, UNIROUEN, CHU Rouen, Inserm U1245, FHU G4 Génomique, Rouen, France;27. Division of Genetics, Department of Pediatrics, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA;28. BC Children’s Hospital Research Institute, BC Children’s Hospital, Vancouver, British Columbia, Canada;29. Department of Pediatrics, University of British Columbia, Vancouver, Canada;30. Adult Metabolic Diseases Clinic, Vancouver General Hospital, Vancouver, Canada;31. Pediatric Genetics Unit, Schneider Children’s Medical Center of Israel, Petach Tikva, Israel;32. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel;33. Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands;34. Genetica AG, Zürich, Switzerland;35. Dr. Seyedhassani Medical Genetic Center, Yazd, Iran;36. KaryoGen, Isfahan, Iran;37. Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, PA;38. Department of Neurosurgery, Program on Neurogenetics, Yale School of Medicine, Yale University, New Haven, CT;39. Masonic Medical Research Institute, Utica, NY;40. Children Growth Disorder Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran;41. Department of Medical Genetics, Next Generation Genetic Polyclinic, Mashhad, Iran;42. Molecular and Clinical Sciences Institute, St. George''s, University of London, London, United Kingdom;43. Innovative Medical Research Center, Mashhad Branch, Islamic Azad University, Mashhad, Iran;44. Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds, United Kingdom;45. Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands;46. MGZ - Medizinisch Genetisches Zentrum, Munich, Germany;47. Human Genetics and Genome Research Division, Department of Clinical Genetics, National Research Centre, Cairo, Egypt;48. Invitae, San Francisco, CA;49. Laboratory of Medical Genetics, Tor Vergata Hospital, Rome, Italy;50. Autophagy Laboratory, Department of Molecular Biology, Interfaculty Institute of Cell Biology, Eberhard Karls University Tuebingen, Tuebingen, Germany;51. Medical Genetics Department, Bambino Gesù Children''s Hospital, IRCCS, Rome, Italy;52. Genetics and Rare Diseases Research Division, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy;53. West Midlands Regional Genetics Service and Birmingham Health Partners, Birmingham, United Kingdom;54. Women''s and Children’s NHS Trust, Birmingham, United Kingdom;55. Castle Hill Hospital, Cottingham, Hull, United Kingdom;56. Department of Clinical and Molecular Genetics, University Hospital Vall d''Hebron, Barcelona, Spain;57. Medicine Genetics Group, Valle Hebron Research Institute, Barcelona, Spain;58. Division of Pediatric Neurology, Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia;59. Department of Pediatrics, College of Medicine, AlMughtaribeen University, Khartoum, Sudan;60. GeneDx, Gaithersburg, MD;61. Institute of Human Genetics and Applied Genomics University of Tübingen, Tübingen, Germany;62. Centre for Rare Diseases, University of Tübingen, Tübingen, Germany;63. Department of Pediatrics, Cincinnati Children’s Hospital, Cincinnati, OH;64. Division of Genetics, Birth Defects and Metabolism, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL;65. Department of Pediatrics, Feinberg School of Medicine of Northwestern University, Chicago, IL;66. Department of Anatomy and Cell Biology College of Medicine, Alfaisal University, Riyadh, Saudi Arabia |
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| Abstract: | PurposeProtein arginine methyltransferase 7 (PRMT7) is a member of a family of enzymes that catalyzes the methylation of arginine residues on several protein substrates. Biallelic pathogenic PRMT7 variants have previously been associated with a syndromic neurodevelopmental disorder characterized by short stature, brachydactyly, intellectual developmental disability, and seizures. To our knowledge, no comprehensive study describes the detailed clinical characteristics of this syndrome. Thus, we aim to delineate the phenotypic spectrum of PRMT7-related disorder.MethodsWe assembled a cohort of 51 affected individuals from 39 different families, gathering clinical information from 36 newly described affected individuals and reviewing data of 15 individuals from the literature.ResultsThe main clinical characteristics of the PRMT7-related syndrome are short stature, mild to severe developmental delay/intellectual disability, hypotonia, brachydactyly, and distinct facial morphology, including bifrontal narrowing, prominent supraorbital ridges, sparse eyebrows, short nose with full/broad nasal tip, thin upper lip, full and everted lower lip, and a prominent or squared-off jaw. Additional variable findings include seizures, obesity, nonspecific magnetic resonance imaging abnormalities, eye abnormalities (i.e., strabismus or nystagmus), and hearing loss.ConclusionThis study further delineates and expands the molecular, phenotypic spectrum and natural history of PRMT7-related syndrome characterized by a neurodevelopmental disorder with skeletal, growth, and endocrine abnormalities. |
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| Keywords: | Chromatinopathy Mendelian disorders of the epigenetic machinery PRMT7 Syndromic neurodevelopmental disorder Syndromic obesity |
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