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Genomic landscape of balanced cytogenetic abnormalities in subjects with multiple congenital anomalies

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dc.contributor.authorRedin, Claire
dc.contributor.authorBrand, Harrison
dc.contributor.authorCollins, Ryan
dc.contributor.authorHanscom, Carrie
dc.contributor.authorVamsee, Pillalamarri
dc.contributor.authorKammin, Tammy
dc.contributor.authorMitchell, E.
dc.contributor.authorHodge, J.C.
dc.contributor.authorSchilit, S.
dc.contributor.authorCurall, B.B.
dc.contributor.authorPereira, S.
dc.contributor.authorSeabra, C.
dc.contributor.authorStone, M.
dc.contributor.authorLawless, W.
dc.contributor.authorLucente, D.
dc.contributor.authorAntolik, C.
dc.contributor.authorHochstenbach, R.
dc.contributor.authorRenkens, I.
dc.contributor.authorBrilstra, E.
dc.contributor.authorVergult, S.
dc.contributor.authorMenten, B.
dc.contributor.authorJanssens, S.
dc.contributor.authorCallewaert, B.
dc.contributor.authorD’heedene, A.
dc.contributor.authorD’hooghe, M
dc.contributor.authorRoelens, F.
dc.contributor.authorvan de Kamp, J.
dc.contributor.authorNieuwint, A.
dc.contributor.authorPoddighe, P.J
dc.contributor.authorvan Ravenswaaij-Arts, C.
dc.contributor.authorRump, P.
dc.contributor.authorvan Essen, T.
dc.contributor.authorFreixo, J.
dc.contributor.authorDavid, Dezső
dc.contributor.authorLiao, E.C.
dc.contributor.authorLeew, N. de
dc.contributor.authorBrunner, H.G.
dc.contributor.authorKloosterman, W.
dc.contributor.authorThorland, E.C.
dc.contributor.authorMorton, C.C.
dc.contributor.authorGusella, J.F.
dc.contributor.authorTalkowski, M E.
dc.date.accessioned2017-03-03T17:34:31Z
dc.date.available2017-03-03T17:34:31Z
dc.date.issued2016
dc.descriptionAbstract publicado em: Eur J Hum Gen.2016;24(S1):4. PL2.1pt_PT
dc.description.abstractBalanced chromosomal abnormalities (BCAs) represent a unique class of genomic variation that involves large rearrangement of the chromosomes. To date their detection has been limited to cytogenetic resolution as most first-tier genetic screening methods are blind to their presence. We defined the genomic landscape of de novo BCAs associated with human congenial anomalies in 235 subjects using whole-genome sequencing. We observed that 22% of all BCAs harbored additional cryptic complexity, ranging from three breakpoints to chromothripsis events involving up to 57 breakpoints. Compared to random expectations, BCAs were more likely to occur between loci in close physical proximity in the nucleus, and their breakpoints were significantly enriched for evolutionarily constrained and embryonically expressed genes. From our convergent genomic interpretation using orthogonal datasets, we predict that the congenital anomaly phenotype was likely attributable to the BCA in at least 30% of subjects. An additional 4% of BCAs disrupted long-range regulatory regions such as topologically associating domains (TADs) resulting in position effects on genes associated with specific clinical manifestations that were compatible with the proband sequenced here. Remarkably, we observed a cluster of six independent translocations that disrupted a TAD and consequently altered MEF2C expression, mimicking the 5q14.3 microdeletion syndrome. These results suggest that de novo BCAs represent a highly penetrant class of genomic variation associated with congenital anomalies, and that nucleotide resolution offers insights into phenotypic prediction from direct gene disruption and alteration of long-range regulatory domains that are likely to be a significant source of causal variation in human disease.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.urihttp://hdl.handle.net/10400.18/4463
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/pt_PT
dc.subjectDoenças Genéticaspt_PT
dc.subjectDoenças Genómicaspt_PT
dc.subjectBalanced Chromosomal Abnormalitiespt_PT
dc.subjectCytogenetic Abnormalitiespt_PT
dc.subjectCongenital Anomaliespt_PT
dc.titleGenomic landscape of balanced cytogenetic abnormalities in subjects with multiple congenital anomaliespt_PT
dc.typeconference object
dspace.entity.typePublication
oaire.citation.conferencePlaceBarcelona, Espanhapt_PT
oaire.citation.titleEuropean Journal Human Genetics Conference, 21-24 May 2016pt_PT
rcaap.rightsopenAccesspt_PT
rcaap.typeconferenceObjectpt_PT

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