Overgrowth disorders are a heterogeneous group of conditions characterized by increased growth parameters and other variable clinical features such as intellectual disability and facial dysmorphism1. To identify new causes of human overgrowth, we performed exome sequencing in ten proband-parent trios and detected two de novo DNMT3A mutations. We identified 11 additional de novo mutations by sequencing DNMT3A in a further 142 individuals with overgrowth. The mutations alter residues in functional DNMT3A domains, and protein modeling suggests that they interfere with domain-domain interactions and histone binding. Similar mutations were not present in 1,000 UK population controls (13/152 cases versus 0/1,000 controls; P < 0.0001). Mutation carriers had a distinctive facial appearance, intellectual disability and greater height. DNMT3A encodes a DNA methyltransferase essential for establishing methylation during embryogenesis and is commonly somatically mutated in acute myeloid leukemia2,3,4. Thus, DNMT3A joins an emerging group of epigenetic DNA- and histone-modifying genes associated with both developmental growth disorders and hematological malignancies5.
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Protein Data Bank
We thank the families for their participation in our research and the physicians and nurses who recruited them. Samples were collected through the Childhood Overgrowth Collaboration; a full list of collaborators is presented in the Supplementary Note. We are grateful to M. Warren-Perry, D. Dudakia and J. Bull for assistance in recruitment and to E. Moran (New York University Hospital for Joint Diseases) and A. Murray (University Hospital of Wales) for their clinical input for COG1770 and COG0109, respectively. We thank A. Strydom for assistance in preparing the manuscript. We are grateful to G. Lunter and M. Münz (Wellcome Trust Centre for Human Genetics, Oxford University) for their contributions to the development of the custom annotation tool SAVANT. We acknowledge use of services provided by the Institute of Cancer Research Genetics Core Facility, which is managed by S.H. and N.R. We acknowledge National Health Service (NHS) funding to the Royal Marsden/Institute of Cancer Research National Institute for Health Research (NIHR) Biomedical Research Centre. We also thank Mariani Foundation Milan for supporting the clinical activity of Genetica Clinica Pediatrica, Fondazione MBBM, AO San Gerardo Monza. This research was supported by the Wellcome Trust (100210/Z/12/Z) and by the Institute of Cancer Research, London.
Integrated supplementary information
Supplementary Tables 1 and 2, Supplementary Figure 1 and Supplementary Note