Functional and epigenetic phenotypes of humans and mice with DNMT3A Overgrowth Syndrome

Amanda M. Smith, Taylor A. LaValle, Marwan Shinawi, Sai M. Ramakrishnan, Haley J. Abel, Cheryl A. Hill, Nicole M. Kirkland, Michael P. Rettig, Nichole M. Helton, Sharon E. Heath, Francesca Ferraro, David Y. Chen, Sangeeta Adak, Clay F. Semenkovich, Diana L. Christian, Jenna R. Martin, Harrison W. Gabel, Christopher A. Miller and Timothy J. Ley ()
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Amanda M. Smith: Washington University School of Medicine
Taylor A. LaValle: Washington University School of Medicine
Marwan Shinawi: Washington University School of Medicine
Sai M. Ramakrishnan: Washington University School of Medicine
Haley J. Abel: Washington University School of Medicine
Cheryl A. Hill: University of Missouri School of Medicine
Nicole M. Kirkland: University of Missouri School of Medicine
Michael P. Rettig: Washington University School of Medicine
Nichole M. Helton: Washington University School of Medicine
Sharon E. Heath: Washington University School of Medicine
Francesca Ferraro: Washington University School of Medicine
David Y. Chen: Washington University School of Medicine
Sangeeta Adak: Washington University School of Medicine
Clay F. Semenkovich: Washington University School of Medicine
Diana L. Christian: Washington University School of Medicine
Jenna R. Martin: Washington University School of Medicine
Harrison W. Gabel: Washington University School of Medicine
Christopher A. Miller: Washington University School of Medicine
Timothy J. Ley: Washington University School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: Abstract Germline pathogenic variants in DNMT3A were recently described in patients with overgrowth, obesity, behavioral, and learning difficulties (DNMT3A Overgrowth 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.

Date: 2021
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DOI: 10.1038/s41467-021-24800-7

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