Growth disrupting mutations in epigenetic regulatory molecules are associated with abnormalities of epigenetic aging

Jeffries, Aaron R., Maroofian, Reza, Salter, Claire G., Chioza, Barry A., Cross, Harold E., Patton, Michael A., Dempster, Emma, Temple, I. Karen, Mackay, Deborah J.G., Rezwan, Faisal I., Aksglaede, Lise, Baralle, Diana, Dabir, Tabib, Hunter, Matthew F., Kamath, Arveen, Kumar, Ajith, Newbury-Ecob, Ruth, Selicorni, Angelo, Springer, Amanda, Van Maldergem, Lionel, Varghese, Vinod, Yachelevich, Naomi, Tatton-Brown, Katrina, Mill, Jonathan, Crosby, Andrew H. and Baple, Emma L. 2019. Growth disrupting mutations in epigenetic regulatory molecules are associated with abnormalities of epigenetic aging. Genome Research 29 (7) , pp. 1057-1066. 10.1101/gr.243584.118

Preview

PDF - Accepted Post-Print Version Download (1MB) | Preview

Abstract

Germline 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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Cold Spring Harbor Laboratory Press
ISSN:	1088-9051
Date of First Compliant Deposit:	7 February 2020
Date of Acceptance:	24 May 2019
Last Modified:	16 Nov 2023 07:07
URI:	https://orca.cardiff.ac.uk/id/eprint/129418

Citation Data

Cited 19 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item