Contribution of rare copy number variants to isolated human malformations

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  • dc.contributor.author Serra Juhé, Clara, 1984-ca
  • dc.contributor.author Rodríguez Santiago, Benjamínca
  • dc.contributor.author Cuscó Martí, Ivon, 1973-ca
  • dc.contributor.author Vendrell, Teresaca
  • dc.contributor.author Camats, Núriaca
  • dc.contributor.author Torán, Núriaca
  • dc.contributor.author Pérez Jurado, Luis Albertoca
  • dc.date.accessioned 2015-05-12T09:47:17Z
  • dc.date.available 2015-05-12T09:47:17Z
  • dc.date.issued 2012ca
  • dc.description.abstract Background: Congenital malformations are present in approximately 2–3% of liveborn babies and 20% of stillborn fetuses. The mechanisms underlying the majority of sporadic and isolated congenital malformations are poorly understood, although it is hypothesized that the accumulation of rare genetic, genomic and epigenetic variants converge to deregulate developmental networks. Methodology/Principal Findings: We selected samples from 95 fetuses with congenital malformations not ascribed to a specific syndrome (68 with isolated malformations, 27 with multiple malformations). Karyotyping and Multiplex Ligation-dependent Probe Amplification (MLPA) discarded recurrent genomic and cytogenetic rearrangements. DNA extracted from the affected tissue (46%) or from lung or liver (54%) was analyzed by molecular karyotyping. Validations and inheritance were obtained by MLPA. We identified 22 rare copy number variants (CNV) [>100 kb, either absent (n = 7) or very uncommon (n = 15, <1/2,000) in the control population] in 20/95 fetuses with congenital malformations (21%), including 11 deletions and 11 duplications. One of the 9 tested rearrangements was de novo while the remaining were inherited from a healthy parent. The highest frequency was observed in fetuses with heart hypoplasia (8/17, 62.5%), with two events previously related with the phenotype. Double events hitting candidate genes were detected in two samples with brain malformations. Globally, the burden of deletions was significantly higher in fetuses with malformations compared to controls./nConclusions/Significance: Our data reveal a significant contribution of rare deletion-type CNV, mostly inherited but also de novo, to human congenital malformations, especially heart hypoplasia, and reinforce the hypothesis of a multifactorial etiology in most cases.en
  • dc.description.sponsorship This work was supported by grants from the Spanish Ministry of Health (PI042063), the CIBERER (Centro de Investigación Biomédica en Red de Enfermedades Raras)(U735-3) and the VI Framework Programme of the European Union (LSHG-CT-2006-037627). CS-J and BR-S were supported by predoctoral (FIS FI08/00365) and posdoctoral fellowships (FIS CD06/00019) of the Fondo de Investigación Sanitaria, respectivelyen
  • dc.format.mimetype application/pdfca
  • dc.identifier.citation Serra-Juhé C, Rodríguez-Santiago B, Cuscó I, Vendrell T, Camats N, Toran N, Pérez-Jurado LA. Contribution of rare copy number variants to isolated human malformations. PLoS ONE. 2012;7(10):e45530. DOI: 10.1371/journal.pone.0045530ca
  • dc.identifier.doi http://dx.doi.org/10.1371/journal.pone.0045530
  • dc.identifier.uri http://hdl.handle.net/10230/23561
  • dc.language.iso engca
  • dc.publisher Public Library of Science (PLoS)ca
  • dc.relation.ispartof PLoS ONE. 2012;7(10):e45530
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/FP6/37627ca
  • dc.rights © 2012 Serra-Juhé et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are crediteden
  • dc.rights.accessRights info:eu-repo/semantics/openAccessca
  • dc.rights.uri https://creativecommons.org/licenses/by/4.0/
  • dc.subject.other Cromosomes humansca
  • dc.subject.other ADNca
  • dc.subject.other Variació (Biologia)ca
  • dc.title Contribution of rare copy number variants to isolated human malformationsen
  • dc.type info:eu-repo/semantics/articleca
  • dc.type.version info:eu-repo/semantics/publishedVersionca

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