Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability

Nat Genet. 2014 Apr;46(4):385-8. doi: 10.1038/ng.2917.

Katrina Tatton-Brown ¹, Sheila Seal ², Elise Ruark ², Jenny Harmer ³, Emma Ramsay ², Silvana Del Vecchio Duarte ², Anna Zachariou ², Sandra Hanks ², Eleanor O'Brien ², Lise Aksglaede ⁴, Diana Baralle ⁵, Tabib Dabir ⁶, Blanca Gener ⁷, David Goudie ⁸, Tessa Homfray ⁹, Ajith Kumar ¹⁰, Daniela T Pilz ¹¹, Angelo Selicorni ¹², I Karen Temple ⁵, Lionel Van Maldergem ¹³, Naomi Yachelevich ¹⁴, Childhood Overgrowth Consortium, Robert van Montfort ³, Nazneen Rahman ¹⁵

Affiliations

1 1] Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK. [2] Cancer Genetics Unit, Royal Marsden Hospital, London, UK. [3] Medical Genetics, St George's University of London, London, UK.
2 Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.
3 Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, Institute of Cancer Research, London, UK.
4 Department of Clinical Genetics, Copenhagen University Hospital, Copenhagen, Denmark.
5 Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK.
6 Northern Ireland Regional Genetics Centre, Clinical Genetics Service, Belfast City Hospital, Belfast, UK.
7 Servicio de Genética, BioCruces Health Research Institute, Hospital Universitario Cruces, Bizkaia, Spain.
8 Department of Human Genetics, Ninewells Hospital and Medical School, Dundee, UK.
9 Medical Genetics, St George's University of London, London, UK.
10 North East Thames Regional Genetics Service, Great Ormond Street Hospital, London, UK.
11 Institute of Medical Genetics, University Hospital of Wales, Cardiff, UK.
12 Ambulatorio di Genetica Clinica Pediatrica, Clinica Pediatrica dell'Università di Milano Bicocca, La Fondazione Monza e Brianza il Bambino e La Sua Mamma (MBBM), Azienda Ospedaliera (AO), San Gerado, Monza, Italy.
13 Centre de Génétique Humaine, Université de Franche-Comté, Besançon, France.
14 Clinical Genetics Services, New York University Hospitals Center, New York University, New York, New York, USA.
15 1] Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK. [2] Cancer Genetics Unit, Royal Marsden Hospital, London, UK.

PMID: 24614070 DOI: 10.1038/ng.2917

Abstract

Overgrowth disorders are a heterogeneous group of conditions characterized by increased growth parameters and Other variable clinical features such as intellectual disability and facial dysmorphism. 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 leukemia. Thus, DNMT3A joins an emerging group of epigenetic DNA- and histone-modifying genes associated with both developmental growth disorders and hematological malignancies.

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