Recessive loss of DIAPH1 function causes a progressive neurodevelopmental syndrome with variable immunological involvement
Genetics in Medicine, vol. 28, pp. 102551
Abstract
PURPOSE: Biallelic DIAPH1 pathogenic variants cause a neurodevelopmental syndrome occasionally associated with immunodeficiency. This study aims to define the clinical and immunological spectrum of DIAPH1-related neuroimmunological syndrome and explore the gene's developmental role using vertebrate models. METHODS: A total of 53 individuals with biallelic DIAPH1 variants, including 33 previously unreported patients, were studied. Clinical features were analyzed, and functional studies were conducted using knockout models in Danio rerio and Xenopus tropicalis. RESULTS: Clinical features included developmental delay, intellectual disability, progressive microcephaly, cortical visual impairment or blindness, epilepsy, and frequent occipital-predominant brain abnormalities. Almost half suffered from infections, mainly affecting their respiratory tract related to epilepsy and aspiration. Although the majority had normal lymphocyte subsets and serum immunoglobulins, T cell receptor excision circles and naïve T-lymphocyte counts were consistently low. The Xenopus model mirrored growth and eye defects seen in humans, whereas zebrafish exhibited no overt malformations but showed seizure-like behavior in Phenothiazine assays. CONCLUSION: DIAPH1 is critical for neurodevelopment, immune regulation, and DNA repair. The DNA repair defect may influence susceptibility to infection, lymphoma, or treatment-related toxicity. Although absolute T cell numbers are not consistent with SCID, impaired T cell maturation suggests that these patients could be identified by T cell excision circles newborn screening before neurological symptoms develop.
Authors 66
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UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Neuromuscular Diseases, 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, Queen Square Institute of Neurology, University College London, London, United Kingdom. Electronic address: r.maroofian@ucl.ac.uk
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UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London, London, United Kingdom
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Affiliation as printed
European Xenopus Resource Centre, School of the Environment and Life Sciences, University of Portsmouth, Portsmouth, United Kingdom
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Affiliation as printed
Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, United Kingdom
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Affiliation as printed
Department of Cell and Developmental Biology, University College London, Gower Street, London, United Kingdom
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Affiliation as printed
Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt
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Affiliation as printed
Institute of Cancer and Genomic Sciences, College of Medicine and Health, University of Birmingham, Birmingham, United Kingdom
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Affiliation as printed
Department of Immunogenetics, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt
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University of Child Health Sciences
Affiliation as printed
Department of Pediatric Neurology, University of Child Health Sciences, The Children's Hospital Lahore, Lahore, Pakistan
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King Faisal Specialist Hospital & Research Centre
Affiliation as printed
Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
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Affiliation as printed
Department of Pediatrics, Al Makassed Hospital and Al-Quds University, Jerusalem, Palestine
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Affiliation as printed
Kuwait Medical Genetics Centre, Ministry of Health, Sulaibikhat, Kuwait
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UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London, London, United Kingdom
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Boston Children's Hospital · Harvard University
Affiliation as printed
Division of Neuroradiology, Department of Radiology, Boston Children's Hospital, Harvard Medical School, Boston, MA
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Affiliation as printed
Department of Cell and Developmental Biology, University College London, Gower Street, London, United Kingdom
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Affiliation as printed
Department of Cell and Developmental Biology, University College London, Gower Street, London, United Kingdom
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Affiliation as printed
Pediatric Neurology Unit, Department of Pediatrics, Sohag University, Sohag, Egypt
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Affiliation as printed
Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt
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Istituto Giannina Gaslini · University of Genoa
Affiliation as printed
Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genova, Italy; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, Genova, Italy
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Nottingham University Hospitals NHS Trust
Affiliation as printed
Clinical Genetics Service, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom
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UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London, London, United Kingdom
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Affiliation as printed
Department of Pediatrics, Al Makassed Hospital and Al-Quds University, Jerusalem, Palestine
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Research Institute Hospital 12 de Octubre · Hospital Universitario 12 De Octubre
Affiliation as printed
Department of Genetics, "12 de Octubre" University Hospital, Madrid, Spain; Dysmorphology and Genetics Unit (UDISGEN), "12 de Octubre" University Hospital, Madrid, Spain; "12 de Octubre" Hospital Research Institute (imas12), Madrid, Spain
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Research Institute Hospital 12 de Octubre · Hospital Universitario 12 De Octubre
Affiliation as printed
Department of Genetics, "12 de Octubre" University Hospital, Madrid, Spain; Dysmorphology and Genetics Unit (UDISGEN), "12 de Octubre" University Hospital, Madrid, Spain; "12 de Octubre" Hospital Research Institute (imas12), Madrid, Spain
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King Faisal Specialist Hospital & Research Centre
Affiliation as printed
Department of Translational Genomics, Genomic Medicine Centre of Excellence (GMCoE), King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
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King Faisal Specialist Hospital & Research Centre
Affiliation as printed
Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
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Affiliation as printed
Kuwait Medical Genetics Centre, Ministry of Health, Sulaibikhat, Kuwait
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Affiliation as printed
Albashir Hospital, Amman, Jordan
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Affiliation as printed
Department of Pediatrics and Child Health, Aga Khan University, Karachi, Pakistan
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Leiden University Medical Center · Willem-Alexander Kinderziekenhuis
Affiliation as printed
Willem-Alexander Children's Hospital, Department of Pediatrics, Laboratory for Pediatric Immunology, Leiden University Medical Center, Leiden, The Netherlands
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Dagmar Berghuis Aachen Division of Pediatric Immunology and Stem Cell Transplantation Department of Pediatrics, Willem-Alexander Children's Hospital
Leiden University Medical Center · Willem-Alexander Kinderziekenhuis
Affiliation as printed
Division of Pediatric Immunology and Stem Cell Transplantation, Department of Pediatrics, Willem-Alexander Children's Hospital, Leiden University Medical Center, Leiden, The Netherlands
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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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Mashhad University of Medical Sciences · Ghaem Hospital
Affiliation as printed
Pediatric Neurology Department, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran; Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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Mashhad University of Medical Sciences
Affiliation as printed
Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Genetic Foundation of Khorasan Razavi, Mashhad, Iran
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Mashhad University of Medical Sciences
Affiliation as printed
Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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Indira Gandhi Institute of Child Health
Affiliation as printed
Department of Pediatric Neurology, Indira Gandhi Institute of Child Health, Bangalore, India
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Indira Gandhi Institute of Child Health
Affiliation as printed
Department of Pediatric Neurology, Indira Gandhi Institute of Child Health, Bangalore, India
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Friedrich-Alexander-Universität Erlangen-Nürnberg
Affiliation as printed
Department of Pediatrics and Adolescent Medicine, Pediatric Neurology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
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Friedrich-Alexander-Universität Erlangen-Nürnberg · Universitätsklinikum Erlangen
Affiliation as printed
Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Centre for Rare Diseases Erlangen (ZSEER), University Hospital Erlangen, Erlangen, Germany
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Friedrich-Alexander-Universität Erlangen-Nürnberg · Universitätsklinikum Erlangen
Affiliation as printed
Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
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Shahid Beheshti University · Shahid Beheshti University of Medical Sciences
Affiliation as printed
Genomic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Shahid Beheshti University · Shahid Beheshti University of Medical Sciences
Affiliation as printed
Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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University of L'Aquila · European Brain Research Institute
Affiliation as printed
Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy; European Brain Research Institute (EBRI), Rome, Italy
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Affiliation as printed
Department of Pediatrics, College of Medicine, Kuwait University, Safat, Kuwait
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Affiliation as printed
Department of Cell and Developmental Biology, University College London, Gower Street, London, United Kingdom
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Affiliation as printed
Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, United Kingdom
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Affiliation as printed
Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, United Kingdom
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Oulu University Hospital · University of Oulu
Affiliation as printed
Research Unit of Clinical Medicine, University of Oulu, Oulu, Finland; Department of Children and Adolescents, Medical Research Center, Oulu University Hospital, Biocenter Oulu, University of Oulu, Oulu, Finland
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Oulu University Hospital · University of Oulu
Affiliation as printed
Research Unit of Clinical Medicine, University of Oulu, Oulu, Finland; Division of Pediatric Neurology, Department of Children and Adolescents, Medical Research Center, Oulu University Hospital, Oulu, Finland
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Oulu University Hospital · University of Oulu
Affiliation as printed
Research Unit of Clinical Medicine, University of Oulu, Oulu, Finland; Division of Pediatric Neurology, Department of Children and Adolescents, Medical Research Center, Oulu University Hospital, Oulu, Finland
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Oulu University Hospital · University of Oulu
Affiliation as printed
Research Unit of Internal Medicine and Biomedicine, University of Oulu, Oulu, Finland; ERN-RITA Core Center Member, RITAFIN Consortium, Infectious Diseases Clinic, Oulu University Hospital, Oulu, Finland
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Birmingham Children's Hospital · University of Birmingham
Affiliation as printed
Institute of Cancer and Genomic Sciences, College of Medicine and Health, University of Birmingham, Birmingham, United Kingdom; Department of Pediatric Hematology, Birmingham Children's Hospital, Birmingham, United Kingdom
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Sheffield Children's NHS Foundation Trust · Sheffield Children's Hospital
Affiliation as printed
Pediatric Immunology, Allergy and Infectious Diseases, Sheffield Children's Hospital NHS Foundation Trust, Sheffield, United Kingdom
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Mashhad University of Medical Sciences
Affiliation as printed
Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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Boston Children's Hospital · Harvard University
Affiliation as printed
Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA
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Affiliation as printed
Department of Cell and Developmental Biology, University College London, Gower Street, London, United Kingdom
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University of Child Health Sciences
Affiliation as printed
Department of Pediatric Neurology, University of Child Health Sciences, The Children's Hospital Lahore, Lahore, Pakistan
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University of California San Diego · Rady Children's Institute for Genomic Medicine
Affiliation as printed
Department of Neuroscience, Rady Children's Institute for Genomic Medicine, University of California San Diego, San Diego, CA
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Kuwait University · Ministry of Health
Affiliation as printed
Kuwait Medical Genetics Centre, Ministry of Health, Sulaibikhat, Kuwait; Department of Pediatrics, College of Medicine, Kuwait University, Safat, Kuwait
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King Faisal Specialist Hospital & Research Centre
Affiliation as printed
Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
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Affiliation as printed
Institute of Cancer and Genomic Sciences, College of Medicine and Health, University of Birmingham, Birmingham, United Kingdom
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UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London, London, United Kingdom
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Affiliation as printed
European Xenopus Resource Centre, School of the Environment and Life Sciences, University of Portsmouth, Portsmouth, United Kingdom
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Affiliation as printed
Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, United Kingdom
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Henry Houlden corresponding
UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London, London, United Kingdom. Electronic address: h.houlden@ucl.ac.uk
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