TY - JOUR
T1 - Growth disrupting mutations in epigenetic regulatory molecules are associated with abnormalities of epigenetic aging
AU - Jeffries, Aaron R.
AU - Maroofian, Reza
AU - Salter, Claire G.
AU - Chioza, Barry A.
AU - Cross, Harold E.
AU - Patton, Michael A.
AU - Dempster, Emma
AU - Karen Temple, I.
AU - Mackay, Deborah J.G.
AU - Rezwan, Faisal I.
AU - Aksglaede, Lise
AU - Baralle, Diana
AU - Dabir, Tabib
AU - Hunter, Matthew F.
AU - Kamath, Arveen
AU - Kumar, Ajith
AU - Newbury-Ecob, Ruth
AU - Selicorni, Angelo
AU - Springer, Amanda
AU - Van Maldergem, Lionel
AU - Varghese, Vinod
AU - Yachelevich, Naomi
AU - Tatton-Brown, Katrina
AU - Mill, Jonathan
AU - Crosby, Andrew H.
AU - Baple, Emma L.
N1 - Funding Information:
We thank the Amish families for participating in this study and the Amish community for their continued support of the Windows of Hope project. The work was supported by the Newlife Foundation for Disabled Children (Ref: SG/16-17/02, to C.G.S., A.R.J., A.H.C., and E.L.B.), Medical Research Council (MRC) grant G1001931 (to E.L.B.), MRC grant G1002279 (to A.H.C.), and MRC grants MR/ M008924/1 and MR/K013807/1 (to J.M.).
Publisher Copyright:
© 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/.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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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U2 - 10.1101/gr.243584.118
DO - 10.1101/gr.243584.118
M3 - Article
C2 - 31160375
AN - SCOPUS:85068837261
VL - 29
SP - 1057
EP - 1066
JO - PCR Methods and Applications
JF - PCR Methods and Applications
SN - 1088-9051
IS - 7
ER -