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Identification of rare de novo epigenetic variations in congenital disorders

2018-05-25Journal article Open access
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dc.contributor.authorBarbosa, M.
dc.contributor.authorJoshi, R.
dc.contributor.authorGarg, P.
dc.contributor.authorMartin-Trujillo, A.
dc.contributor.authorPatel, N.
dc.contributor.authorJadhav, B.
dc.contributor.authorWatson, C.
dc.contributor.authorGibson, W.
dc.contributor.authorChetnik, K.
dc.contributor.authorTessereau, C.
dc.contributor.authorMei, H.
dc.contributor.authorDe Rubeis, S.
dc.contributor.authorReichert, J.
dc.contributor.authorLopes, F.
dc.contributor.authorVissers, L.
dc.contributor.authorKleefstra, T.
dc.contributor.authorGrice, D.
dc.contributor.authorEdelmann, L.
dc.contributor.authorSoares, G.
dc.contributor.authorMaciel, P.
dc.contributor.authorBrunner, H.
dc.contributor.authorBuxbaum, J.
dc.contributor.authorGelb, B.
dc.contributor.authorSharp, A.
dc.date.accessioned2020-02-03T12:01:03Z
dc.date.available2020-02-03T12:01:03Z
dc.date.issued2018-05-25
dc.description.abstractCertain human traits such as neurodevelopmental disorders (NDs) and congenital anomalies (CAs) are believed to be primarily genetic in origin. However, even after whole-genome sequencing (WGS), a substantial fraction of such disorders remain unexplained. We hypothesize that some cases of ND-CA are caused by aberrant DNA methylation leading to dysregulated genome function. Comparing DNA methylation profiles from 489 individuals with ND-CAs against 1534 controls, we identify epivariations as a frequent occurrence in the human genome. De novo epivariations are significantly enriched in cases, while RNAseq analysis shows that epivariations often have an impact on gene expression comparable to loss-of-function mutations. Additionally, we detect and replicate an enrichment of rare sequence mutations overlapping CTCF binding sites close to epivariations, providing a rationale for interpreting non-coding variation. We propose that epivariations contribute to the pathogenesis of some patients with unexplained ND-CAs, and as such likely have diagnostic relevance.pt_PT
dc.description.sponsorshipThe authors are grateful to the patients and families who participated in this study and to the collaborators who supported patient recruitment. This work was supported by NIH grant HG006696 and research grant 6-FY13-92 from the March of Dimes to A.J.S., grant HL098123 to B.D.G. and A.J.S., Gulbenkian Programme for Advanced Medical Education and the Portuguese Foundation for Science and Technology (SFRH/BDINT/51549/ 2011, PIC/IC/83026/2007, PIC/IC/83013/2007, SFRH/BD/90167/2012, Portugal) to P.M., F.L., and M.B., by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER) (NORTE-01-0145-FEDER-000013) to P.M., a Beatriu de Pinos Postdoctoral Fellowship to R.S.J. (2011BP-A00515), and a Seaver Foundation fellowship to S.D.R. The views expressed are those of the authors and do not necessarily reflect those of the National Heart, Lung, and Blood Institute or the National Institutes of Health. Research reported in this paper was supported by the Office of Research Infrastructure of the National Institutes of Health under award number S10OD018522. This work was supported in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationNat Commun. 2018 May 25;9(1):2064pt_PT
dc.identifier.doi10.1038/s41467-018-04540-xpt_PT
dc.identifier.issn2041-1723
dc.identifier.urihttp://hdl.handle.net/10400.16/2305
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherNature Researchpt_PT
dc.relationIdiopathic mental retardation: evaluation of a CGH microarray strategy for genetic diagnosis
dc.relationFINDING NOVEL GENES FOR INTELLECTUAL DISABILITY BY WHOLE EXOME SEQUENCING
dc.relation.publisherversionhttps://www.nature.com/articles/s41467-018-04540-xpt_PT
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/pt_PT
dc.titleIdentification of rare de novo epigenetic variations in congenital disorderspt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleIdiopathic mental retardation: evaluation of a CGH microarray strategy for genetic diagnosis
oaire.awardTitleFINDING NOVEL GENES FOR INTELLECTUAL DISABILITY BY WHOLE EXOME SEQUENCING
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/5876-PPCDTI/PIC%2FIC%2F83026%2F2007/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/5876-PPCDTI/PIC%2FIC%2F83013%2F2007/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBD%2F90167%2F2012/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/SFRH/SFRH%2FBDINT%2F51549%2F2011/PT
oaire.citation.conferencePlaceEnglandpt_PT
oaire.citation.issue1pt_PT
oaire.citation.startPage2064pt_PT
oaire.citation.titleNature communicationspt_PT
oaire.citation.volume9pt_PT
oaire.fundingStream5876-PPCDTI
oaire.fundingStream5876-PPCDTI
oaire.fundingStreamSFRH
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
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