Null variants and deletions in BRWD3 cause an X‐linked syndrome of mild–moderate intellectual disability,macrocephaly, and obesity: A series of 17 patients |
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| Authors: | Philip J. Ostrowski Anna Zachariou Chey Loveday Diana Baralle Edward Blair Sofia Douzgou Michael Field Alison Foster Claire Kyle Katherine Lachlan Sahar Mansour Swati Naik Gillian Rea Sarah Smithson Yves Sznajer Elizabeth Thompson Trevor Cole Katrina Tatton‐Brown |
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| Affiliation: | 1. South West Thames Regional Genetics Service, St George's University NHS Foundation Trust, London, UK;2. Division of Clinical Studies, Institute of Cancer Research, London, UK;3. Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK;4. Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK;5. Faculty of Medicine, Human Development and Health, University of Southampton, Southampton, UK;6. Oxford Centre for Genomic Medicine, ACE Building, Nuffield Orthopaedic Centre, Oxford, UK;7. Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK;8. Division of Evolution and Genomic Sciences, School of Biological Sciences, University of Manchester, Manchester, UK;9. Genetics of Learning Disability Service, Hunter Genetics, Waratah, New South Wales, Australia;10. West Midlands Regional Genetics Service, Birmingham Women's NHS Foundation Trust, Birmingham, UK;11. Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University Hospitals NHS Foundation Trust, Manchester, UK;12. Clinical Genetics, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK;13. Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast, UK;14. Department of Clinical Genetics, St Michael's Hospital, Bristol, UK;15. Center for Human Genetics, Cliniques Universitaires St‐Luc, Universite Catholique de Louvain, Brussels, Belgium;16. South Australian Clinical Genetics Service, Women's and Children's Hospital, Adelaide, South Australia, Australia;17. Institute of Molecular and Clinical Sciences, St George's University of London, London, UK;18. Katrina Tatton‐Brown, St George's University of London, Cranmer Terrace, London, UK. SW17 0QT |
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| Abstract: | BRWD3 has been described as a cause of X‐linked intellectual disability, but relatively little is known about the specific phenotype. We report the largest BRWD3 patient series to date, comprising 17 males with 12 distinct null variants and 2 partial gene deletions. All patients presented with intellectual disability, which was classified as moderate (65%) or mild (35%). Behavioral issues were present in 75% of patients, including aggressive behavior, attention deficit/hyperactivity and/or autistic spectrum disorders. Mean head circumference was +2.8 SD (2.8 standard deviations above the mean), and mean BMI was +2.0 SD (in the context of a mean height of +1.3 SD), indicating a predominant macrocephaly/obesity phenotype. Shared facial features included a tall chin, prognathism, broad forehead, and prominent supraorbital ridge. Additional features, reported in a minority (<30%) of patients included cryptorchidism, neonatal hypotonia, and small joint hypermobility. This study delineates the clinical features associated with BRWD3 null variants and partial gene deletions, and suggests that BRWD3 should be included in the differential diagnosis of patients with an overgrowth‐intellectual disability (OGID) phenotype, particularly in male patients with a mild or moderate intellectual disability associated with macrocephaly and/or obesity. |
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| Keywords: |
BRWD3 intellectual disability macrocephaly overgrowth X‐linked |
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