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Nat Genet. 2014 Apr;46(4):385-8. doi: 10.1038/ng.2917. Epub 2014 Mar 9.

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

Author information

  • 11] 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.
  • 2Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.
  • 3Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, Institute of Cancer Research, London, UK.
  • 4Department of Clinical Genetics, Copenhagen University Hospital, Copenhagen, Denmark.
  • 5Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK.
  • 6Northern Ireland Regional Genetics Centre, Clinical Genetics Service, Belfast City Hospital, Belfast, UK.
  • 7Servicio de Genética, BioCruces Health Research Institute, Hospital Universitario Cruces, Bizkaia, Spain.
  • 8Department of Human Genetics, Ninewells Hospital and Medical School, Dundee, UK.
  • 9Medical Genetics, St George's University of London, London, UK.
  • 10North East Thames Regional Genetics Service, Great Ormond Street Hospital, London, UK.
  • 11Institute of Medical Genetics, University Hospital of Wales, Cardiff, UK.
  • 12Ambulatorio 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.
  • 13Centre de Génétique Humaine, Université de Franche-Comté, Besançon, France.
  • 14Clinical Genetics Services, New York University Hospitals Center, New York University, New York, New York, USA.
  • 151] Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK. [2] Cancer Genetics Unit, Royal Marsden Hospital, London, UK.

Erratum in

  • Nat Genet. 2014 Jun;46(6):657.

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.

PMID:
24614070
[PubMed - indexed for MEDLINE]
PMCID:
PMC3981653
Free PMC Article
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