dc.contributor.author | Jeffries, AR | |
dc.contributor.author | Maroofian, R | |
dc.contributor.author | Salter, CG | |
dc.contributor.author | Chioza, BA | |
dc.contributor.author | Cross, HE | |
dc.contributor.author | Patton, MA | |
dc.contributor.author | Dempster, E | |
dc.contributor.author | Karen Temple, I | |
dc.contributor.author | Mackay, D | |
dc.contributor.author | Rezwan, FI | |
dc.contributor.author | Aksglæde, L | |
dc.contributor.author | Baralle, D | |
dc.contributor.author | Dabir, T | |
dc.contributor.author | Hunter, MF | |
dc.contributor.author | Kamath, A | |
dc.contributor.author | Kumar, A | |
dc.contributor.author | Newbury-Ecob, R | |
dc.contributor.author | Selicorni, A | |
dc.contributor.author | Springer, A | |
dc.contributor.author | van Maldergem, L | |
dc.contributor.author | Varghese, V | |
dc.contributor.author | Yachelevich, N | |
dc.contributor.author | Tatton Brown, K | |
dc.contributor.author | Mill, J | |
dc.contributor.author | Crosby, AH | |
dc.contributor.author | Baple, EL | |
dc.date.accessioned | 2019-07-10T09:55:02Z | |
dc.date.issued | 2019-06-03 | |
dc.description.abstract | 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 to 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 fundamentally new insights into aberrant epigenetic mechanisms, the role of epigenetic machinery maintenance and determinants of biological aging in these growth disorders. | en_GB |
dc.description.sponsorship | Newlife Foundation for Disabled Children | en_GB |
dc.description.sponsorship | Medical Research Council | en_GB |
dc.identifier.citation | Published online 3-June-2019 | en_GB |
dc.identifier.doi | 10.1101/gr.243584.118 | |
dc.identifier.grantnumber | Ref: SG/16-17/02 | en_GB |
dc.identifier.grantnumber | G1001931 | en_GB |
dc.identifier.grantnumber | G1002279 | en_GB |
dc.identifier.grantnumber | MR/ M008924/1 | en_GB |
dc.identifier.grantnumber | MR/K013807/1 | en_GB |
dc.identifier.other | gr.243584.118 | |
dc.identifier.uri | http://hdl.handle.net/10871/37917 | |
dc.language.iso | en | en_GB |
dc.publisher | Cold Spring Harbor Laboratory Press | en_GB |
dc.relation.url | https://www.ncbi.nlm.nih.gov/pubmed/31160375 | en_GB |
dc.rights | © 2019 Jeffries et al.; Published by Cold Spring Harbor Laboratory Press
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_GB |
dc.title | Growth disrupting mutations in epigenetic regulatory molecules are associated with abnormalities of epigenetic aging. | en_GB |
dc.type | Article | en_GB |
dc.date.available | 2019-07-10T09:55:02Z | |
exeter.place-of-publication | United States | en_GB |
dc.description | This is the final version. Available from Cold Spring Harbor Laboratory Press via the DOI in this record. | en_GB |
dc.description | The raw and processed primary data sets generated in this study
have been submitted to the NCBI Gene Expression Omnibus
(GEO; https://www.ncbi.nlm.nih.gov/geo/) under accession number GSE128801. R scripts are provided as Supplemental Code S1
and at the following repository: https://github.com/arjeffries/
TBRS2019. | en_GB |
dc.identifier.journal | Genome Research | en_GB |
dc.rights.uri | http://www.rioxx.net/licenses/all-rights-reserved | en_GB |
dcterms.dateAccepted | 2019-05-24 | |
rioxxterms.version | VoR | en_GB |
rioxxterms.licenseref.startdate | 2019-06-03 | |
rioxxterms.type | Journal Article/Review | en_GB |
refterms.dateFCD | 2019-07-10T09:42:27Z | |
refterms.versionFCD | VoR | |
refterms.dateFOA | 2019-07-10T09:55:07Z | |
refterms.panel | A | en_GB |