Growth disrupting mutations in epigenetic regulatory molecules are associated with abnormalities of epigenetic aging
- Aaron R. Jeffries1,
- Reza Maroofian2,
- Claire G. Salter1,3,4,
- Barry A. Chioza1,
- Harold E. Cross5,
- Michael A. Patton1,2,
- Emma Dempster1,
- I. Karen Temple3,4,
- Deborah J.G. Mackay3,
- Faisal I. Rezwan3,
- Lise Aksglaede6,
- Diana Baralle3,4,
- Tabib Dabir7,
- Matthew F. Hunter8,13,
- Arveen Kamath9,
- Ajith Kumar10,
- Ruth Newbury-Ecob11,
- Angelo Selicorni12,
- Amanda Springer8,13,
- Lionel Van Maldergem14,
- Vinod Varghese9,
- Naomi Yachelevich15,
- Katrina Tatton-Brown2,16,17,
- Jonathan Mill1,
- Andrew H. Crosby1 and
- Emma L. Baple1,18
- 1Institute of Biomedical and Clinical Science, University of Exeter Medical School, RILD Wellcome Wolfson Centre, Royal Devon and Exeter NHS Foundation Trust, Exeter, EX2 5DW, United Kingdom;
- 2Genetics Research Centre, Molecular and Clinical Sciences Institute, St. George's University of London, London SW17 0RE, United Kingdom;
- 3Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, United Kingdom;
- 4Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, SO16 5YA, United Kingdom;
- 5Department of Ophthalmology and Vision Science, University of Arizona School of Medicine, Tucson, Arizona 85711, USA;
- 6Department of Clinical Genetics, Copenhagen University Hospital, Blegdamsvej 3B, 2200 Copenhagen N, Denmark;
- 7Northern Ireland Regional Genetics Centre, Clinical Genetics Service, Belfast City Hospital, Belfast, BT9 7AB, United Kingdom;
- 8Monash Genetics, Monash Health, Clayton, Victoria, VIC 3168, Australia;
- 9Institute of Medical Genetics, University Hospital of Wales, Cardiff, CF14 4XN, United Kingdom;
- 10North East Thames Regional Genetics Service and Department of Clinical Genetics, Great Ormond Street Hospital, London, WC1N 3JH, United Kingdom;
- 11University Hospitals Bristol, Department of Clinical Genetics, St Michael's Hospital, Bristol, BS2 8EG, United Kingdom;
- 12UOC Pediatria ASST Lariana, Como, Italy;
- 13Department of Paediatrics, Monash University, Clayton, Victoria, VIC 3168, Australia;
- 14Centre de génétique humaine and Clinical Investigation Center 1431 (INSERM), Université de Franche-Comté, 25000, Besançon, France;
- 15Clinical Genetics Services, New York University Hospitals Center, New York University, New York, New York 10016, USA;
- 16Division of Genetics and Epidemiology, Institute of Cancer Research, London SM2 5NG, United Kingdom;
- 17South West Thames Regional Genetics Service, St. George's University Hospitals NHS Foundation Trust, London SW17 0QT, United Kingdom;
- 18Peninsula Clinical Genetics Service, Royal Devon and Exeter Hospital, Exeter, EX1 2ED, United Kingdom
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.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.243584.118.
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Freely available online through the Genome Research Open Access option.
- Received September 2, 2018.
- Accepted May 24, 2019.
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/.
