Growth disrupting mutations in epigenetic regulatory molecules are associated with abnormalities of epigenetic aging
AuthorJeffries, Aaron R
Salter, Claire G
Chioza, Barry A
Cross, Harold E
Patton, Michael A
Temple, I Karen
Mackay, Deborah J G
Rezwan, Faisal I
Hunter, Matthew F
Van Maldergem, Lionel
Crosby, Andrew H
Baple, Emma L
AffiliationUniv Arizona, Sch Med, Dept Ophthalmol & Vis Sci
MetadataShow full item record
CitationJeffries, A. R., Maroofian, R., Salter, C. G., Chioza, B. A., Cross, H. E., Patton, M. A., ... & Aksglæde, L. (2019). Growth disrupting mutations in epigenetic regulatory molecules are associated with abnormalities of epigenetic aging. Genome research, gr-243584.
Rights© 2019 Jeffries et al. This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
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AbstractGermline mutations in fundamental epigenetic regulatory molecules including DNA methyltransferase 3 alpha (DNMT3A) are commonly associated with growth disorders, whereas somatic mutations are often associated with malignancy. We profiled genome-wide DNA methylation patterns in DNMT3A c.2312G > A; p.(Arg771Gln) carriers in a large Amish sibship with Tatton-Brown-Rahman syndrome (TBRS), their mosaic father, and 15 TBRS patients with distinct pathogenic de novo DNMT3A variants. This defined widespread DNA hypomethylation at specific genomic sites enriched at locations annotated as genes involved in morphogenesis, development, differentiation, and malignancy predisposition pathways. TBRS patients also displayed highly accelerated DNA methylation aging. These findings were most marked in a carrier of the AML-associated driver mutation p.Arg882Cys. Our studies additionally defined phenotype-related accelerated and decelerated epigenetic aging in two histone methyltransferase disorders: NSD1 Sotos syndrome overgrowth disorder and KMT2D Kabuki syndrome growth impairment. Together, our findings provide fundamental new insights into aberrant epigenetic mechanisms, the role of epigenetic machinery maintenance, and determinants of biological aging in these growth disorders.
NoteOpen access article
VersionFinal published version
SponsorsNewlife Foundation for Disabled Children [SG/16-17/02]; Medical Research Council (MRC) [G1001931]; MRC [MR/M008924/1, MR/K013807/1, G1002279]; Amish community
Except where otherwise noted, this item's license is described as © 2019 Jeffries et al. This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
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