ClinVar

Tatton-Brown-Rahman Syndrome

In a patient with Tatton-Brown-Rahman syndrome (TBRS; 615879), Shen et al. (2017) identified a c.2644C-T transition (c.2644C-T, NM_175629.2) in the DNMT3A gene, resulting in an arg882-to-cys (R882C) substitution.

In an 19-year-old Dutch boy with TBRS who developed FAB type M5 acute myelogenous leukemia (AML; 601626) at age 15 years, Hollink et al. (2017) identified a de novo heterozygous germline c.2644C-T transition in the DNMT3A gene, resulting in an arg882-to-cys (R882C) substitution. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Analysis of leukemic cells showed an aberrant karyotype and a somatic PTPN11 mutation (T73I; 176876.0011), but no additional somatic mutations or loss of heterozygosity of the DNMT3A gene. Hollink et al. (2017) suggested that mutations at the R882 residue, which are associated with acute myeloid leukemia in the somatic state, may also predispose germline carriers of the mutation to the development of AML. The authors postulated epigenetic dysregulation as a possible molecular mechanism and suggested that patients with TBRS be followed for hematologic malignancies. Functional studies of the variants were not performed.

In a 6-year-old girl (patient 5) with TBRS, Balci et al. (2020) identified heterozygosity for the recurrent R882C mutation in the DNMT3A gene. The child was previously reported by DeMari et al. (2016) at age 3.5 years with a heterozygous frameshift mutation in the CLTC gene (118955.0001) and a diagnosis of global developmental delay (MRD56; 617854). At age 6 years, the child presented with lymphadenopathy, a mediastinal mass, and hypercalcemia, and was diagnosed with T-cell lymphoblastic lymphoma.

Acute Myeloid Leukemia, Somatic

Of 62 patients with acute myelogenous leukemia (AML; 601626) who were found to have a somatic mutation in the DNMT3A gene, Ley et al. (2010) found that 7 had a C-to-T transition at a CpG dinucleotide, resulting in an arg882-to-cys (R882C) substitution.