Germline mutations in the oncogene EZH2 cause Weaver syndrome and increased human height

Katrina Tatton-Brown 1,2 , Sandra Hanks 1 , Elise Ruark 1 , Anna Zachariou 1 , Silvana Del Vecchio Duarte 1 , Emma Ramsay 1 , Katie Snape 1 , Anne Murray 1 , Elizabeth R Perdeaux 1 , Sheila Seal 1 , Chey Loveday 1 , Siddharth Banka 3 , Carol Clericuzio 4 , Frances Flinter 5 , Alex Magee 6 , Vivienne McConnell 6 , Michael Patton 2 , Wolfgang Raith 7 , Julia Rankin 8 , Miranda Splitt 9 , Volker Strenger 10 , Clare Taylor 11 , Patricia Wheeler 12 , I Karen Temple 13 , Trevor Cole 14 , The Childhood Overgrowth Collaboration 15 , Jenny Douglas 1 and Nazneen Rahman 1 1 Division of Genetics & Epidemiology, Institute of Cancer Research, Sutton, UK 2 Medical Genetics, St George's University of London, London, UK 3 Genetic Medicine, University of Manchester, Manchester, UK 4 Pediatric Genetics, University of New Mexico, Albuquerque, USA 5 Clinical Genetics, Guy's and St Thomas' Foundation Trust, London, UK 6 Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast, Northern Ireland, UK 7 Division of Neonatology, Department of Paediatrics, Medical University, Graz, Austria 8 Peninsula Clinical Genetics Service, Royal Devon and Exeter Foundation NHS Trust, Exeter, UK 9 Institute of Human Genetics, International Centre for Life, Newcastle upon Tyne, UK 10 Department of Paediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria 11 Institute of Medical Genetics, University Hospital of Wales, Cardiff, UK 12 Division of Genetics, Nemours Children's Clinic, Orlando, USA 13 Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK 14 West Midlands Regional Genetics Service, Birmingham Women's Hospital, Birmingham, UK 15 A 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 Correspondence: Professor Nazneen Rahman, email: // // Abstract 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.