Show simple item record

dc.contributor.authorJeffries, Aaron R
dc.contributor.authorMaroofian, Reza
dc.contributor.authorSalter, Claire G
dc.contributor.authorChioza, Barry A
dc.contributor.authorCross, Harold E
dc.contributor.authorPatton, Michael A
dc.contributor.authorDempster, Emma
dc.contributor.authorTemple, I Karen
dc.contributor.authorMackay, Deborah J G
dc.contributor.authorRezwan, Faisal I
dc.contributor.authorAksglaede, Lise
dc.contributor.authorBaralle, Diana
dc.contributor.authorDabir, Tabib
dc.contributor.authorHunter, Matthew F
dc.contributor.authorKamath, Arveen
dc.contributor.authorKumar, Ajith
dc.contributor.authorNewbury-Ecob, Ruth
dc.contributor.authorSelicorni, Angelo
dc.contributor.authorSpringer, Amanda
dc.contributor.authorVan Maldergem, Lionel
dc.contributor.authorVarghese, Vinod
dc.contributor.authorYachelevich, Naomi
dc.contributor.authorTatton-Brown, Katrina
dc.contributor.authorMill, Jonathan
dc.contributor.authorCrosby, Andrew H
dc.contributor.authorBaple, Emma L
dc.date.accessioned2019-08-02T21:42:26Z
dc.date.available2019-08-02T21:42:26Z
dc.date.issued2019-07
dc.identifier.citationJeffries, A. R., Maroofian, R., Salter, C. G., Chioza, B. A., Cross, H. E., Patton, M. A., ... & Aksglæde, L. (2019). Growth disrupting mutations in epigenetic regulatory molecules are associated with abnormalities of epigenetic aging. Genome research, gr-243584.en_US
dc.identifier.issn1088-9051
dc.identifier.pmid31160375
dc.identifier.doi10.1101/gr.243584.118
dc.identifier.urihttp://hdl.handle.net/10150/633640
dc.description.abstractGermline 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.en_US
dc.description.sponsorshipNewlife Foundation for Disabled Children [SG/16-17/02]; Medical Research Council (MRC) [G1001931]; MRC [MR/M008924/1, MR/K013807/1, G1002279]; Amish communityen_US
dc.language.isoenen_US
dc.publisherCOLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPTen_US
dc.rights© 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/.en_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.titleGrowth disrupting mutations in epigenetic regulatory molecules are associated with abnormalities of epigenetic agingen_US
dc.typeArticleen_US
dc.identifier.eissn1549-5469
dc.contributor.departmentUniv Arizona, Sch Med, Dept Ophthalmol & Vis Scien_US
dc.identifier.journalGENOME RESEARCHen_US
dc.description.noteOpen access articleen_US
dc.description.collectioninformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.en_US
dc.eprint.versionFinal published versionen_US
dc.source.journaltitleGenome research
refterms.dateFOA2019-08-02T21:42:27Z


Files in this item

Thumbnail
Name:
Genome Res.-2019-Jeffries-1057 ...
Size:
972.3Kb
Format:
PDF
Description:
Final Published Version

This item appears in the following Collection(s)

Show simple item record

© 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/.
Except where otherwise noted, this item's license is described as © 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/.