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; Timothy J. Ley

doi:10.1038/s41467-021-24800-7

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, Timothy J. Ley

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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 DNMT3A^R882H mutation. A germline mouse model expressing the homologous Dnmt3a^R878H 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.

Original language	English
Article number	4549
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-24800-7
State	Published - Dec 1 2021

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Smith, A. M., LaValle, T. A., Shinawi, M., Ramakrishnan, S. M., Abel, H. J., Hill, C. A., Kirkland, N. M., Rettig, M. P., Helton, N. M., Heath, S. E., Ferraro, F., Chen, D. Y., Adak, S., Semenkovich, C. F., Christian, D. L., Martin, J. R., Gabel, H. W., Miller, C. A., & Ley, T. J. (2021). Functional and epigenetic phenotypes of humans and mice with DNMT3A Overgrowth Syndrome. Nature communications, 12(1), Article 4549. https://doi.org/10.1038/s41467-021-24800-7

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title = "Functional and epigenetic phenotypes of humans and mice with DNMT3A Overgrowth Syndrome",

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.",

author = "Smith, {Amanda M.} and LaValle, {Taylor A.} and Marwan Shinawi and Ramakrishnan, {Sai M.} and Abel, {Haley J.} and Hill, {Cheryl A.} and Kirkland, {Nicole M.} and Rettig, {Michael P.} and Helton, {Nichole M.} and Heath, {Sharon E.} and Francesca Ferraro and Chen, {David Y.} and Sangeeta Adak and Semenkovich, {Clay F.} and Christian, {Diana L.} and Martin, {Jenna R.} and Gabel, {Harrison W.} and Miller, {Christopher A.} and Ley, {Timothy J.}",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

day = "1",

doi = "10.1038/s41467-021-24800-7",

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Smith, AM, LaValle, TA, Shinawi, M, Ramakrishnan, SM, Abel, HJ, Hill, CA, Kirkland, NM, Rettig, MP, Helton, NM, Heath, SE, Ferraro, F , Chen, DY , Adak, S , Semenkovich, CF, Christian, DL, Martin, JR, Gabel, HW , Miller, CA & Ley, TJ 2021, 'Functional and epigenetic phenotypes of humans and mice with DNMT3A Overgrowth Syndrome', Nature communications, vol. 12, no. 1, 4549. https://doi.org/10.1038/s41467-021-24800-7

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T1 - Functional and epigenetic phenotypes of humans and mice with DNMT3A Overgrowth Syndrome

AU - Smith, Amanda M.

AU - LaValle, Taylor A.

AU - Shinawi, Marwan

AU - Ramakrishnan, Sai M.

AU - Abel, Haley J.

AU - Hill, Cheryl A.

AU - Kirkland, Nicole M.

AU - Rettig, Michael P.

AU - Helton, Nichole M.

AU - Heath, Sharon E.

AU - Ferraro, Francesca

AU - Chen, David Y.

AU - Adak, Sangeeta

AU - Semenkovich, Clay F.

AU - Christian, Diana L.

AU - Martin, Jenna R.

AU - Gabel, Harrison W.

AU - Miller, Christopher A.

AU - Ley, Timothy J.

PY - 2021/12/1

Y1 - 2021/12/1

N2 - 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.

AB - 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.

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

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