Growth disrupting mutations in epigenetic regulatory molecules are associated with abnormalities of epigenetic aging
- Aaron Richard Jeffries1,
- Reza Maroofian2,
- Claire G Salter1,
- Barry A Chioza1,
- Harold E Cross3,
- Michael A Patton2,
- Emma Dempster1,
- I Karen Temple4,
- Deborah Mackay4,
- Faisal I Rezwan4,
- Lise Aksglæde5,
- Dianne Baralle4,
- Tabib Dabir6,
- Matthew Frank Hunter7,
- Arveen Kamath8,
- Ajith Kumar9,
- Ruth Newbury-Ecob10,
- Angelo Selicorni11,
- Amanda Springer12,
- Lionel van Maldergem13,
- Vinod Varghese8,
- Naomi Yachelevich14,
- Katrina Tatton Brown15,
- Jonathan Mill1,
- Andrew H Crosby1 and
- Emma L Baple1,16
- 1 University of Exeter Medical School;
- 2 St Georges University of London;
- 3 University of Arizona School of Medicine;
- 4 University of Southampton;
- 5 University of Copenhagen;
- 6 Belfast City Hospital;
- 7 Monash Health;
- 8 University Hospital of Wales;
- 9 Great Ormond Street Hospital;
- 10 University of Bristol;
- 11 UOC Pediatria ASST Laraina;
- 12 Monash University;
- 13 Centre de Génétique Humaine and Integrative and Cognitive Neuroscience Research Unit;
- 14 New York University;
- 15 Institute of Cancer Research
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 to 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 fundamentally new insights into aberrant epigenetic mechanisms, the role of epigenetic machinery maintenance and determinants of biological aging in these growth disorders.
- Received September 2, 2018.
- Accepted May 24, 2019.
- Published by Cold Spring Harbor Laboratory Press
This manuscript is Open Access.
This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International license), as described at http://creativecommons.org/licenses/by/4.0/.
