Abstract
Germline pathogenic variants in DNMT3A were recently described in patients with overgrowth, obesity, behavioral, and learning difficulties (DNMT3AOvergrowth Syndrome/DOS). Somatic mutations in the DNMT3A gene are also the most common cause of clonal hematopoiesis, and can initiate acute myeloid leukemia (AML). Using whole genome bisulfite sequencing, we studied DNA methylation in peripheral blood cells of 11 DOS patients and found a focal, canonical hypomethylation phenotype, which is most severe with the dominant negative DNMT3AR882H mutation. A germline mouse model expressing the homologous Dnmt3aR878H mutation phenocopies most aspects of the human DOS syndrome, including the methylation phenotype and an increased incidence of spontaneous hematopoietic malignancies, suggesting that all aspects of this syndrome are caused by this mutation.
Highlights
Germline pathogenic variants in DNMT3A were recently described in patients with overgrowth, obesity, behavioral, and learning difficulties (DNMT3A Overgrowth Syndrome/DNMT3A overgrowth syndrome (DOS))
We describe DNA methylation alterations and their consequences in human patients, and a mouse model of the DNMT3A Overgrowth Syndrome (DOS)
This model supports the observation that patients with clonal hematopoiesis caused by mutations in DNMT3A can live for many years without clinical progression to AML14–16,37
Summary
Germline pathogenic variants in DNMT3A were recently described in patients with overgrowth, obesity, behavioral, and learning difficulties (DNMT3A Overgrowth Syndrome/DOS). The first report of DNMT3A overgrowth syndrome (DOS, called Tatton–Brown–Rahman Syndrome; TBRS; MIM 615879) described a syndrome of increased growth, defined as height and/or head circumference at least two standard deviations above the mean, associated with facial dysmorphism and intellectual disability occurring in patients with de novo heterozygous germline mutations in DNMT3A1. 13/152 patients with overgrowth had mutations in the DNMT3A gene, and all mutations were located within the functional domains of the protein. Somatic mutations in DNMT3A are the most common cause of clonal hematopoiesis[14,15,16] and are the most common initiating mutation in AML patients with a normal karyotype[17,18,19]
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