Detection of a mosaic DNMT3A variant with potential neurodevelopmental and malignancy risks in monozygotic twins: a case report

The DNMT3A gene encodes DNA methyltransferase 3 alpha, which is essential for epigenetic modifications. Pathogenic germline DNMT3A variants are associated with autosomal dominant Tatton-Brown-Rahman syndrome (TBRS), an overgrowth condition characterized by tall stature, unique facial features, intellectual disability, musculoskeletal abnormalities, and seizures. Pathogenic somatic DNMT3A variants, most commonly the p.Arg882His (p.R882H) variant, are associated with age-related clonal hematopoiesis resulting in abnormal white blood cell proliferation and an increased risk for acute myeloid leukemia. Germline variants at amino acid residue 882 have been observed in individuals with TBRS, including those with hematologic malignancies, potentially indicating an increased risk of malignancy associated with these variants. However, the clinical implications of post-zygotic mosaic DNMT3A variants, including their contribution to neurological phenotypes and malignancy risk, remain poorly understood. We report monozygotic male twins who underwent research-based exome sequencing due to a history of epilepsy, without intellectual or developmental disability. Exome sequencing revealed a pathogenic DNMT3A p.R882H variant at approximately 35% and 34% variant allele fractions in blood-derived DNA from both twins. The variant was absent in DNA from buccal samples of both individuals and from parental buccal and blood samples, suggesting mosaicism. Following multidisciplinary research team review of variant-level evidence, the DNMT3A mosaic variant was determined to be a reportable pathogenic finding. However, it was emphasized that the clinical relevance of the variant is unclear due to its possible role in the patients’ epilepsy history and the uncertain future risk for hematological malignancy. These cases highlight the complexity of interpreting post-zygotic mosaic DNMT3A variants, particularly the common p.R882H variant, and underscore the need for additional studies to provide clear guidelines regarding their reporting and longitudinal medical management.