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

• Published in: American journal of medical genetics. Part A Vol. 173; no. 11; pp. 3022 - 3028
• Main Authors: Shen, Wei, Heeley, Jennifer M., Carlston, Colleen M., Acuna‐Hidalgo, Rocio, Nillesen, Willy M., Dent, Karin M., Douglas, Ganka V., Levine, Kara L., Bayrak‐Toydemir, Pinar, Marcelis, Carlo L., Shinawi, Marwan, Carey, John C.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01-11-2017
• Subjects: Acute myeloid leukemia; Blood cancer; Codon; DNA (Cytosine-5-)-Methyltransferases - genetics; DNMT3A; exome sequencing; Face - physiopathology; Female; Genetic Predisposition to Disease; Germ-Line Mutation - genetics; hematologic malignancies; Hematologic Neoplasms - genetics; Hematologic Neoplasms - pathology; Humans; Intellectual Disability - genetics; Intellectual Disability - pathology; Male; Mutation; Mutation hot spots; Myeloid leukemia; Phenotype; Tatton–Brown–Rahman syndrome; hematologic malignancies; exome sequencing; Tatton-Brown-Rahman syndrome; DNMT3A
• ISSN: 1552-4825; 1552-4833
• DOI: 10.1002/ajmg.a.38485

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.