Biallelic PRMT7 pathogenic variants are associated with a recognizable syndromic neurodevelopmental disorder with short stature, obesity, and craniofacial and digital abnormalities
Genetics in Medicine, vol. 25, pp. 135–142
Abstract
PURPOSE: Protein 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. METHODS: We 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. RESULTS: The 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. CONCLUSION: This 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.
Authors 66
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UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom
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Nottingham University Hospitals NHS Trust
Affiliation as printed
Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust, City Hospital Campus, Nottingham, United Kingdom
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Istituto Giannina Gaslini · University of Genoa
Affiliation as printed
Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy; Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy
Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
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Centre for Human Genetics · National Institute for Health and Care Research · University of Oxford · NIHR Oxford Biomedical Research Centre
Affiliation as printed
Genomic Medicine theme, Oxford Biomedical Research Centre, NIHR, Oxford, Oxfordshire, United Kingdom; Wellcome Centre for Human Genetics, Oxford University, Oxford, Oxfordshire, United Kingdom
Genomic Medicine theme, Oxford Biomedical Research Centre, NIHR, Oxford, Oxfordshire, United Kingdom
Wellcome Centre for Human Genetics, Oxford University, Oxford, Oxfordshire, United Kingdom
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University of Isfahan · UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom; Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran; Palindrome, Isfahan, Iran
Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom
Palindrome, Isfahan, Iran
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Affiliation as printed
Section of Medical Genetics, Children's Specialist Hospital, King Fahad Medical, City, Riyadh, Saudi Arabia
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Leiden University Medical Center
Affiliation as printed
Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
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University of California San Diego · Rady Children's Hospital-San Diego
Affiliation as printed
Division of Medical Genetics, Department of Pediatrics, University of California, and Rady Children's Hospital, San Diego, CA
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Southampton General Hospital · Princess Anne Hospital · University Hospital Southampton NHS Foundation Trust · University of Southampton
Affiliation as printed
Wessex Clinical Genetics Service, Princess Anne Hospital, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom; Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, United Kingdom
Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, United Kingdom
Wessex Clinical Genetics Service, Princess Anne Hospital, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom
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Shahid Sadoughi University of Medical Sciences and Health Services
Affiliation as printed
Medical Genetics Research Center, Shahid Sadoughi University of Medical Science, Yazd, Iran
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Brown University · Rhode Island Hospital · Hasbro Children's Hospital
Affiliation as printed
Division of Human Genetics, Warren Alpert Medical School of Brown University, Hasbro Children's Hospital/Rhode Island Hospital, Providence, RI
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University Hospital Leipzig · Leipzig University
Affiliation as printed
Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany
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Affiliation as printed
Institute of Medical Genetics, University of Zurich, Zurich, Switzerland
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University of California San Diego · Rady Children's Hospital-San Diego
Affiliation as printed
Division of Medical Genetics, Department of Pediatrics, University of California, and Rady Children's Hospital, San Diego, CA
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Ochsner Health System · The University of Queensland
Affiliation as printed
Section of Medical Genetics, Department of Pediatrics, Ochsner Health System and University of Queensland, New Orleans, LA
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Ochsner Health System · The University of Queensland
Affiliation as printed
Section of Medical Genetics, Department of Pediatrics, Ochsner Health System and University of Queensland, New Orleans, LA
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Affiliation as printed
Department of Pediatrics and Molecular and Human Genetics, Baylor College of Medicine, San Antonio, TX
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Johannes Kepler University of Linz
Affiliation as printed
Department of Medical Genetics, Kepler University Hospital Med Campus IV, Johannes Kepler University, Linz, Austria
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Children's Hospital of Orange County
Affiliation as printed
Children's Hospital of Orange County, Orange, CA; Genetics Center, Orange, California
Children's Hospital of Orange County, Orange, CA
Genetics Center, Orange, California
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Affiliation as printed
Department of Neurology, Boston Children's Hospital, Boston, MA; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA
Department of Neurology, Boston Children's Hospital, Boston, MA
Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA
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Affiliation as printed
Department of Genetics and Reference Center for Developmental Disorders, Normandie University, UNIROUEN, CHU Rouen, Inserm U1245, FHU G4 Génomique, Rouen, France
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Affiliation as printed
Department of Genetics and Reference Center for Developmental Disorders, Normandie University, UNIROUEN, CHU Rouen, Inserm U1245, FHU G4 Génomique, Rouen, France
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University of California, Los Angeles
Affiliation as printed
Division of Genetics, Department of Pediatrics, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA
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University of British Columbia · BC Children's Hospital · BC Children's Hospital Research Institute
Affiliation as printed
BC Children's Hospital Research Institute, BC Children's Hospital, Vancouver, British Columbia, Canada; Department of Pediatrics, University of British Columbia, Vancouver, Canada
BC Children's Hospital Research Institute, BC Children's Hospital, Vancouver, British Columbia, Canada
Department of Pediatrics, University of British Columbia, Vancouver, Canada
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Affiliation as printed
Adult Metabolic Diseases Clinic, Vancouver General Hospital, Vancouver, Canada
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Tel Aviv University · Schneider Children's Medical Center
Affiliation as printed
Pediatric Genetics Unit, Schneider Children's Medical Center of Israel, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Pediatric Genetics Unit, Schneider Children's Medical Center of Israel, Petach Tikva, Israel
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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Affiliation as printed
Section of Medical Genetics, Children's Specialist Hospital, King Fahad Medical, City, Riyadh, Saudi Arabia
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Radboud University Medical Center
Affiliation as printed
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
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Affiliation as printed
Genetica AG, Zürich, Switzerland
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Shahid Sadoughi University of Medical Sciences and Health Services
Affiliation as printed
Medical Genetics Research Center, Shahid Sadoughi University of Medical Science, Yazd, Iran
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Affiliation as printed
Dr. Seyedhassani Medical Genetic Center, Yazd, Iran
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Affiliation as printed
Palindrome, Isfahan, Iran; KaryoGen, Isfahan, Iran; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, PA
Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, PA
KaryoGen, Isfahan, Iran
Palindrome, Isfahan, Iran
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Affiliation as printed
Dr. Seyedhassani Medical Genetic Center, Yazd, Iran
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Yale University · Masonic Medical Research Laboratory
Affiliation as printed
Department of Neurosurgery, Program on Neurogenetics, Yale School of Medicine, Yale University, New Haven, CT; Masonic Medical Research Institute, Utica, NY
Department of Neurosurgery, Program on Neurogenetics, Yale School of Medicine, Yale University, New Haven, CT
Masonic Medical Research Institute, Utica, NY
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Affiliation as printed
Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran; Palindrome, Isfahan, Iran
Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
Palindrome, Isfahan, Iran
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Shahid Sadoughi University of Medical Sciences and Health Services
Affiliation as printed
Children Growth Disorder Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
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UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom
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Istituto Giannina Gaslini · University of Genoa
Affiliation as printed
Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy; Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy
Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
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St George's, University of London · Islamic Azad University, Mashhad
Affiliation as printed
Department of Medical Genetics, Next Generation Genetic Polyclinic, Mashhad, Iran; Molecular and Clinical Sciences Institute, St. George's, University of London, London, United Kingdom; Innovative Medical Research Center, Mashhad Branch, Islamic Azad University, Mashhad, Iran
Department of Medical Genetics, Next Generation Genetic Polyclinic, Mashhad, Iran
Innovative Medical Research Center, Mashhad Branch, Islamic Azad University, Mashhad, Iran
Molecular and Clinical Sciences Institute, St. George's, University of London, London, United Kingdom
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Istituto Giannina Gaslini · UCL Queen Square Institute of Neurology · University College London · University of Genoa
Affiliation as printed
Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy; Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom
Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy
Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
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Centre for Human Genetics · National Institute for Health and Care Research · University of Oxford · NIHR Oxford Biomedical Research Centre
Affiliation as printed
Genomic Medicine theme, Oxford Biomedical Research Centre, NIHR, Oxford, Oxfordshire, United Kingdom; Wellcome Centre for Human Genetics, Oxford University, Oxford, Oxfordshire, United Kingdom
Genomic Medicine theme, Oxford Biomedical Research Centre, NIHR, Oxford, Oxfordshire, United Kingdom
Wellcome Centre for Human Genetics, Oxford University, Oxford, Oxfordshire, United Kingdom
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Affiliation as printed
Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds, United Kingdom
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Radboud University Nijmegen · Maastricht University Medical Centre · Radboud University Medical Center · Maastricht University
Affiliation as printed
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands
Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
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Affiliation as printed
MGZ - Medizinisch Genetisches Zentrum, Munich, Germany
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Affiliation as printed
Human Genetics and Genome Research Division, Department of Clinical Genetics, National Research Centre, Cairo, Egypt
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Affiliation as printed
Invitae, San Francisco, CA
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Affiliation as printed
Laboratory of Medical Genetics, Tor Vergata Hospital, Rome, Italy
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Affiliation as printed
Autophagy Laboratory, Department of Molecular Biology, Interfaculty Institute of Cell Biology, Eberhard Karls University Tuebingen, Tuebingen, Germany
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Bambino Gesù Children's Hospital · Istituti di Ricovero e Cura a Carattere Scientifico
Affiliation as printed
Medical Genetics Department, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy; Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
Medical Genetics Department, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
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Affiliation as printed
Institute of Medical Genetics, University of Zurich, Zurich, Switzerland
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Affiliation as printed
Department of Neurosurgery, Program on Neurogenetics, Yale School of Medicine, Yale University, New Haven, CT
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Birmingham Women’s and Children’s NHS Foundation Trust
Affiliation as printed
West Midlands Regional Genetics Service and Birmingham Health Partners, Birmingham, United Kingdom; Women's and Children's NHS Trust, Birmingham, United Kingdom
West Midlands Regional Genetics Service and Birmingham Health Partners, Birmingham, United Kingdom
Women's and Children's NHS Trust, Birmingham, United Kingdom
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University of California, Los Angeles
Affiliation as printed
Division of Genetics, Department of Pediatrics, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA
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Chapel Allerton Hospital · Castle Hill Hospital
Affiliation as printed
Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds, United Kingdom; Castle Hill Hospital, Cottingham, Hull, United Kingdom
Castle Hill Hospital, Cottingham, Hull, United Kingdom
Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds, United Kingdom
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Vall d'Hebron Institut de Recerca · Vall d'Hebron Hospital Universitari
Affiliation as printed
Department of Clinical and Molecular Genetics, University Hospital Vall d'Hebron, Barcelona, Spain; Medicine Genetics Group, Valle Hebron Research Institute, Barcelona, Spain
Department of Clinical and Molecular Genetics, University Hospital Vall d'Hebron, Barcelona, Spain
Medicine Genetics Group, Valle Hebron Research Institute, Barcelona, Spain
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Affiliation as printed
Department of Pediatrics and Molecular and Human Genetics, Baylor College of Medicine, San Antonio, TX
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Ochsner Health System · The University of Queensland
Affiliation as printed
Section of Medical Genetics, Department of Pediatrics, Ochsner Health System and University of Queensland, New Orleans, LA
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King Saud University · AlMughtaribeen University
Affiliation as printed
Division of Pediatric Neurology, Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia; Department of Pediatrics, College of Medicine, AlMughtaribeen University, Khartoum, Sudan
Department of Pediatrics, College of Medicine, AlMughtaribeen University, Khartoum, Sudan
Division of Pediatric Neurology, Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia
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Affiliation as printed
GeneDx, Gaithersburg, MD
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Affiliation as printed
GeneDx, Gaithersburg, MD
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Affiliation as printed
GeneDx, Gaithersburg, MD
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Affiliation as printed
Institute of Human Genetics and Applied Genomics University of Tübingen, Tübingen, Germany; Centre for Rare Diseases, University of Tübingen, Tübingen, Germany
Centre for Rare Diseases, University of Tübingen, Tübingen, Germany
Institute of Human Genetics and Applied Genomics University of Tübingen, Tübingen, Germany
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Northwestern University · Cincinnati Children's Hospital Medical Center · Lurie Children's Hospital
Affiliation as printed
Department of Pediatrics, Cincinnati Children's Hospital, Cincinnati, OH; Division of Genetics, Birth Defects and Metabolism, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL; Department of Pediatrics, Feinberg School of Medicine of Northwestern University, Chicago, IL
Department of Pediatrics, Cincinnati Children's Hospital, Cincinnati, OH
Department of Pediatrics, Feinberg School of Medicine of Northwestern University, Chicago, IL
Division of Genetics, Birth Defects and Metabolism, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL
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Alfaisal University · King Faisal Specialist Hospital & Research Centre
Affiliation as printed
Department of Translational Genomics, Center for Genomics Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia; Department of Anatomy and Cell Biology College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
Department of Anatomy and Cell Biology College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
Department of Translational Genomics, Center for Genomics Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
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UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom
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Reza Maroofian corresponding
UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom. Electronic address: r.maroofian@ucl.ac.uk
Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom
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