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Genome Res. 2019 Jul;29(7):1057-1066. doi: 10.1101/gr.243584.118. Epub 2019 Jun 3.

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

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Institute 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.
Genetics Research Centre, Molecular and Clinical Sciences Institute, St. George's University of London, London SW17 0RE, United Kingdom.
Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, United Kingdom.
Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, SO16 5YA, United Kingdom.
Department of Ophthalmology and Vision Science, University of Arizona School of Medicine, Tucson, Arizona 85711, USA.
Department of Clinical Genetics, Copenhagen University Hospital, Blegdamsvej 3B, 2200 Copenhagen N, Denmark.
Northern Ireland Regional Genetics Centre, Clinical Genetics Service, Belfast City Hospital, Belfast, BT9 7AB, United Kingdom.
Monash Genetics, Monash Health, Clayton, Victoria, VIC 3168, Australia.
Department of Paediatrics, Monash University, Clayton, Victoria, VIC 3168, Australia.
Institute of Medical Genetics, University Hospital of Wales, Cardiff, CF14 4XN, United Kingdom.
North East Thames Regional Genetics Service and Department of Clinical Genetics, Great Ormond Street Hospital, London, WC1N 3JH, United Kingdom.
University Hospitals Bristol, Department of Clinical Genetics, St Michael's Hospital, Bristol, BS2 8EG, United Kingdom.
UOC Pediatria ASST Lariana, Como, Italy.
Centre de génétique humaine and Clinical Investigation Center 1431 (INSERM), Université de Franche-Comté, 25000, Besançon, France.
Clinical Genetics Services, New York University Hospitals Center, New York University, New York, New York 10016, USA.
Division of Genetics and Epidemiology, Institute of Cancer Research, London SM2 5NG, United Kingdom.
South West Thames Regional Genetics Service, St. George's University Hospitals NHS Foundation Trust, London SW17 0QT, United Kingdom.
Peninsula Clinical Genetics Service, Royal Devon and Exeter Hospital, Exeter, EX1 2ED, United Kingdom.


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.

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