Germline mutations in the oncogene EZH2 cause Weaver syndrome and increased human height
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1Division of Genetics & Epidemiology, Institute of Cancer Research, Sutton, UK
2Medical Genetics, St George’s University of London, London, UK
3Genetic Medicine, University of Manchester, Manchester, UK
4Pediatric Genetics, University of New Mexico, Albuquerque, USA
5Clinical Genetics, Guy’s and St Thomas’ Foundation Trust, London, UK
6Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast, Northern Ireland, UK
7Division of Neonatology, Department of Paediatrics, Medical University, Graz, Austria
8Peninsula Clinical Genetics Service, Royal Devon and Exeter Foundation NHS Trust, Exeter, UK
9Institute of Human Genetics, International Centre for Life, Newcastle upon Tyne, UK
10Department of Paediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
11Institute of Medical Genetics, University Hospital of Wales, Cardiff, UK
12Division of Genetics, Nemours Children's Clinic, Orlando, USA
13Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK
14West Midlands Regional Genetics Service, Birmingham Women’s Hospital, Birmingham, UK
15A full list of members appears in the Supplementary Appendix
Received: December 17, 2011; Accepted: December 20, 2011; Published: December 21, 2011;
Keywords: EZH2, Weaver syndrome, height, myeloid malignancies, histone methyltransferase
Professor Nazneen Rahman, email:
The biological processes controlling human growth are diverse, complex and poorly understood. Genetic factors are important and human height has been shown to be a highly polygenic trait to which common and rare genetic variation contributes. Weaver syndrome is a human overgrowth condition characterised by tall stature, dysmorphic facial features, learning disability and variable additional features. We performed exome sequencing in four individuals with Weaver syndrome, identifying a mutation in the histone methyltransferase, EZH2, in each case. Sequencing of EZH2 in additional individuals with overgrowth identified a further 15 mutations. The EZH2 mutation spectrum in Weaver syndrome shows considerable overlap with the inactivating somatic EZH2 mutations recently reported in myeloid malignancies. Our data establish EZH2 mutations as the cause of Weaver syndrome and provide further links between histone modifications and regulation of human growth.
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