RT Journal
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
JF Genome Research 
JO Genome Research 
YR 2019 
FD July 01 
VO 29 
IS 7 
SP 1057 
OP 1066 
DO 10.1101/gr.243584.118 
UL http://genome.cshlp.org/content/29/7/1057.abstract 
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.