Esther R Berko1, Megan T Cho2, Christine Eng3, Yunru Shao3,4, David A Sweetser5, Jessica Waxler5, Nathaniel H Robin6, Fallon Brewer6, Sandra Donkervoort7, Payam Mohassel7, Carsten G Bönnemann7, Martin Bialer8, Christine Moore8, Lynne A Wolfe9,10, Cynthia J Tifft9,10, Yufeng Shen11, Kyle Retterer2, Francisca Millan2, Wendy K Chung1,12. 1. Department of Pediatrics, Columbia University Medical Center, New York, New York, USA. 2. GeneDx, Gaithersburg, Maryland, USA. 3. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA. 4. Texas Children's Hospital, Houston, Texas, USA. 5. Massachusetts General Hospital, Boston, Massachusetts, USA. 6. University of Alabama at Birmingham, Birmingham, Alabama, USA. 7. National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA. 8. Cohen Children's Medical Center of NY, New Hyde Park, New York, USA. 9. Office of the Clinical Director, National Institutes of Health, Bethesda, Maryland, USA. 10. Undiagnosed Diseases Program, National Institutes of Health, Bethesda, Maryland, USA. 11. Departments of Systems Biology and Biomedical Informatics, Columbia University Medical Center, New York, New York, USA. 12. Department of Medicine, Columbia University Medical Center, New York, New York, USA.
Abstract
BACKGROUND: The causes of intellectual disability (ID) are diverse and de novo mutations are increasingly recognised to account for a significant proportion of ID. METHODS AND RESULTS: In this study, we performed whole exome sequencing on a large cohort of patients with ID or neurodevelopmental delay and identified four novel de novo predicted deleterious missense variants in HECW2 in six probands with ID/developmental delay and hypotonia. Other common features include seizures, strabismus, nystagmus, cortical visual impairment and dysmorphic facial features. HECW2 is an ubiquitin ligase that stabilises p73, a crucial mediator of neurodevelopment and neurogenesis. CONCLUSION: This study implicates pathogenic genetic variants in HECW2 as potential causes of neurodevelopmental disorders in humans. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
BACKGROUND: The causes of intellectual disability (ID) are diverse and de novo mutations are increasingly recognised to account for a significant proportion of ID. METHODS AND RESULTS: In this study, we performed whole exome sequencing on a large cohort of patients with ID or neurodevelopmental delay and identified four novel de novo predicted deleterious missense variants in HECW2 in six probands with ID/developmental delay and hypotonia. Other common features include seizures, strabismus, nystagmus, cortical visual impairment and dysmorphic facial features. HECW2 is an ubiquitin ligase that stabilises p73, a crucial mediator of neurodevelopment and neurogenesis. CONCLUSION: This study implicates pathogenic genetic variants in HECW2 as potential causes of neurodevelopmental disorders in humans. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
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