title: Acute myeloid leukemia-associated DNMT3A p.Arg882His mutation in a patient with Tatton-Brown-Rahman overgrowth syndrome as a constitutional mutation.
abstract: DNA methylation plays a critical role in both embryonic development and tumorigenesis and is mediated through various DNA methyltransferases. Constitutional mutations in the de novo DNA methyltransferase DNMT3A cause a recently identified Tatton-Brown-Rahman overgrowth syndrome (TBRS). Somatically acquired mutations in DNMT3A are causally associated with acute myeloid leukemia (AML), and p.Arg882His represents the most prevalent hotspot. So far, no patients with TBRS have been reported to have subsequently developed AML. Here, we report a live birth and the survival of a female with the TBRS phenotype who had a heterozygous constitutional DNMT3A mutation at the AML somatic mutation hotspot p.Arg882His in her DNA from peripheral blood and buccal tissue. Her characteristic features at birth included hypotonia, narrow palpebral fissures, ventricular septal defect, umbilical hernia, sacral cyst, Chiari type I anomaly. At the age of 6 years, she exhibited overgrowth (> 3 SD) and round face and intellectual disability. This report represents the first documentation of the same variant (DNMT3A p.Arg882His) as both the constitutional mutation associated with TBRS and the somatic mutation hotspot of AML. The observation neither confirms nor denies the notion that mutations responsible for TBRS and those for AML might share the same mode of action. Larger data sets are required to determine whether TBRS patients with constitutional DNMT3A mutations are at an increased risk for AML. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Division of Medical Genetics, National Center for Child Health and Development, Tokyo, Japan.
authors.forename: Rika
authors.initials: R
authors.lastname: Kosaki
authors.affiliation: Division of Neulorogy, National Center for Child Health and Development, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Terashima
authors.affiliation: Division of Neulorogy, National Center for Child Health and Development, Tokyo, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Kubota
authors.affiliation: Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Kosaki
mesh_terms: D019943:Amino Acid Substitution; D002675:Child, Preschool; D003062:Codon; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D004252:DNA Mutational Analysis; D005260:Female; D056726:Genetic Association Studies; D057238:Growth Charts; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics; D009154:Mutation; D010641:Phenotype; D013577:Syndrome
chemical_list: D003062:Codon; C000717967:DNMT3A protein, human; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A
keywords: AML; DNMT3A; acute myeloid leukemia; overgrowth