The spectrum of DNMT3A variants in Tatton–Brown–Rahman syndrome overlaps with that in hematologic malignancies

Wei Shen, Jennifer M. Heeley, Colleen M. Carlston, Rocio Acuna-Hidalgo, Willy M. Nillesen, Karin M. Dent, Ganka V. Douglas, Kara L. Levine, Pinar Bayrak-Toydemir, Carlo L. Marcelis, Marwan Shinawi, John C. Carey

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

De novo, germline variants in DNMT3A cause Tatton–Brown–Rahman syndrome (TBRS). This condition is characterized by overgrowth, distinctive facial appearance, and intellectual disability. Somatic DNMT3A variants frequently occur in hematologic malignances, particularly acute myeloid leukemia. The Arg882 residue is the most common site of somatic DNMT3A variants, and has also been altered in patients with TBRS. Here we present three additional patients with this disorder attributed to DNMT3A germline variants that disrupt the Arg882 codon, suggesting that this codon may be a germline mutation hotspot in this disorder. Furthermore, based on the investigation of previously reported variants in patients with TBRS, we found overlap in the spectrum of DNMT3A variants observed in this disorder and somatic variants in hematological malignancies.

Original languageEnglish
Pages (from-to)3022-3028
Number of pages7
JournalAmerican Journal of Medical Genetics, Part A
Volume173
Issue number11
DOIs
StatePublished - Nov 2017

Keywords

  • DNMT3A
  • Tatton–Brown–Rahman syndrome
  • exome sequencing
  • hematologic malignancies

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