TY  - JOUR
A1  - Jeffries, Aaron R.
A1  - Maroofian, Reza
A1  - Salter, Claire G.
A1  - Chioza, Barry A.
A1  - Cross, Harold E.
A1  - Patton, Michael A.
A1  - Dempster, Emma
A1  - Temple, I. Karen
A1  - Mackay, Deborah J.G.
A1  - Rezwan, Faisal I.
A1  - Aksglaede, Lise
A1  - Baralle, Diana
A1  - Dabir, Tabib
A1  - Hunter, Matthew F.
A1  - Kamath, Arveen
A1  - Kumar, Ajith
A1  - Newbury-Ecob, 
Ruth
A1  - Selicorni, Angelo
A1  - Springer, Amanda
A1  - Van Maldergem, 
Lionel
A1  - Varghese, Vinod
A1  - Yachelevich, Naomi
A1  - Tatton-Brown, Katrina
A1  - Mill, Jonathan
A1  - Crosby, Andrew H.
A1  - Baple, Emma L.
T1  - Growth disrupting mutations in epigenetic regulatory molecules are associated with abnormalities of epigenetic aging
Y1  - 2019/07/01 
JF  - Genome Research 
JO  - Genome Research 
SP  - 1057 
EP  - 1066 
DO  - 10.1101/gr.243584.118 
VL  - 29 
IS  - 7 
UR  - http://genome.cshlp.org/content/29/7/1057.abstract 
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. 
ER  -