title: Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability.
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.
authors.affiliation: 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.
authors.forename: Katrina
authors.initials: K
authors.lastname: Tatton-Brown
authors.affiliation: Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.
authors.forename: Sheila
authors.initials: S
authors.lastname: Seal
authors.affiliation: Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.
authors.forename: Elise
authors.initials: E
authors.lastname: Ruark
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, Institute of Cancer Research, London, UK.
authors.forename: Jenny
authors.initials: J
authors.lastname: Harmer
authors.affiliation: Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Ramsay
authors.affiliation: Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.
authors.forename: Silvana
authors.initials: S
authors.lastname: Del Vecchio Duarte
authors.affiliation: Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Zachariou
authors.affiliation: Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.
authors.forename: Sandra
authors.initials: S
authors.lastname: Hanks
authors.affiliation: Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.
authors.forename: Eleanor
authors.initials: E
authors.lastname: O'Brien
authors.affiliation: Department of Clinical Genetics, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Lise
authors.initials: L
authors.lastname: Aksglaede
authors.affiliation: Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: Diana
authors.initials: D
authors.lastname: Baralle
authors.affiliation: Northern Ireland Regional Genetics Centre, Clinical Genetics Service, Belfast City Hospital, Belfast, UK.
authors.forename: Tabib
authors.initials: T
authors.lastname: Dabir
authors.affiliation: Servicio de Genética, BioCruces Health Research Institute, Hospital Universitario Cruces, Bizkaia, Spain.
authors.forename: Blanca
authors.initials: B
authors.lastname: Gener
authors.affiliation: Department of Human Genetics, Ninewells Hospital and Medical School, Dundee, UK.
authors.forename: David
authors.initials: D
authors.lastname: Goudie
authors.affiliation: Medical Genetics, St George's University of London, London, UK.
authors.forename: Tessa
authors.initials: T
authors.lastname: Homfray
authors.affiliation: North East Thames Regional Genetics Service, Great Ormond Street Hospital, London, UK.
authors.forename: Ajith
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Institute of Medical Genetics, University Hospital of Wales, Cardiff, UK.
authors.forename: Daniela T
authors.initials: DT
authors.lastname: Pilz
authors.affiliation: 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.
authors.forename: Angelo
authors.initials: A
authors.lastname: Selicorni
authors.affiliation: Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: I Karen
authors.initials: IK
authors.lastname: Temple
authors.affiliation: Centre de Génétique Humaine, Université de Franche-Comté, Besançon, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Van Maldergem
authors.affiliation: Clinical Genetics Services, New York University Hospitals Center, New York University, New York, New York, USA.
authors.forename: Naomi
authors.initials: N
authors.lastname: Yachelevich
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, Institute of Cancer Research, London, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: van Montfort
authors.affiliation: 1] Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK. [2] Cancer Genetics Unit, Royal Marsden Hospital, London, UK.
authors.forename: Nazneen
authors.initials: N
authors.lastname: Rahman
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D001483:Base Sequence; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000090205:DNA Methyltransferase 3A; D059472:Exome / Q000235:genetics; D040461:Gene Components; D006130:Growth Disorders / Q000235:genetics*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D011487:Protein Conformation; D017422:Sequence Analysis, DNA; D013577:Syndrome; D006113:United Kingdom
chemical_list: C000717967:DNMT3A protein, human; D006657:Histones; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A