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dc.contributor.authorJeffries, AR
dc.contributor.authorMaroofian, R
dc.contributor.authorSalter, CG
dc.contributor.authorChioza, BA
dc.contributor.authorCross, HE
dc.contributor.authorPatton, MA
dc.contributor.authorDempster, E
dc.contributor.authorKaren Temple, I
dc.contributor.authorMackay, D
dc.contributor.authorRezwan, FI
dc.contributor.authorAksglæde, L
dc.contributor.authorBaralle, D
dc.contributor.authorDabir, T
dc.contributor.authorHunter, MF
dc.contributor.authorKamath, A
dc.contributor.authorKumar, A
dc.contributor.authorNewbury-Ecob, R
dc.contributor.authorSelicorni, A
dc.contributor.authorSpringer, A
dc.contributor.authorvan Maldergem, L
dc.contributor.authorVarghese, V
dc.contributor.authorYachelevich, N
dc.contributor.authorTatton Brown, K
dc.contributor.authorMill, J
dc.contributor.authorCrosby, AH
dc.contributor.authorBaple, EL
dc.date.accessioned2019-07-10T09:55:02Z
dc.date.issued2019-06-03
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 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.sponsorshipNewlife Foundation for Disabled Childrenen_GB
dc.description.sponsorshipMedical Research Councilen_GB
dc.identifier.citationPublished online 3-June-2019en_GB
dc.identifier.doi10.1101/gr.243584.118
dc.identifier.grantnumberRef: SG/16-17/02en_GB
dc.identifier.grantnumberG1001931en_GB
dc.identifier.grantnumberG1002279en_GB
dc.identifier.grantnumberMR/ M008924/1en_GB
dc.identifier.grantnumberMR/K013807/1en_GB
dc.identifier.othergr.243584.118
dc.identifier.urihttp://hdl.handle.net/10871/37917
dc.language.isoenen_GB
dc.publisherCold Spring Harbor Laboratory Pressen_GB
dc.relation.urlhttps://www.ncbi.nlm.nih.gov/pubmed/31160375en_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.titleGrowth disrupting mutations in epigenetic regulatory molecules are associated with abnormalities of epigenetic aging.en_GB
dc.typeArticleen_GB
dc.date.available2019-07-10T09:55:02Z
exeter.place-of-publicationUnited Statesen_GB
dc.descriptionThis is the final version. Available from Cold Spring Harbor Laboratory Press via the DOI in this record.en_GB
dc.descriptionThe 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.journalGenome Researchen_GB
dc.rights.urihttp://www.rioxx.net/licenses/all-rights-reserveden_GB
dcterms.dateAccepted2019-05-24
rioxxterms.versionVoRen_GB
rioxxterms.licenseref.startdate2019-06-03
rioxxterms.typeJournal Article/Reviewen_GB
refterms.dateFCD2019-07-10T09:42:27Z
refterms.versionFCDVoR
refterms.dateFOA2019-07-10T09:55:07Z
refterms.panelAen_GB


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