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Novel candidate genes and a wide spectrum of structural and point mutations responsible for inherited retinal dystrophies revealed by exome sequencing

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dc.contributor.author de Castro-Miró, Marta
dc.contributor.author Tonda, Raúl
dc.contributor.author Escudero-Ferruz, Paula
dc.contributor.author Andrés, Rosa
dc.contributor.author Mayor-Lorenzo, Andrés
dc.contributor.author Castro, Joaquín
dc.contributor.author Ciccioli, Marcela
dc.contributor.author Hidalgo, Daniel A.
dc.contributor.author Rodríguez-Ezcurra, Juan José
dc.contributor.author Farrando, Jorge
dc.contributor.author Pérez-Santonja, Juan J.
dc.contributor.author Cormand, Bru
dc.contributor.author Marfany, Gemma
dc.contributor.author Gonzàlez-Duarte, Roser
dc.date.accessioned 2023-12-12T06:36:39Z
dc.date.available 2023-12-12T06:36:39Z
dc.date.issued 2016
dc.identifier.citation de Castro-Miró M, Tonda R, Escudero-Ferruz P, Andrés R, Mayor-Lorenzo A, Castro J, et al. Novel candidate genes and a wide spectrum of structural and point mutations responsible for inherited retinal dystrophies revealed by exome sequencing. PLoS ONE. 2016 Dec 22;11(12):e0168966. DOI: 10.1371/journal.pone.0168966
dc.identifier.issn 1932-6203
dc.identifier.uri http://hdl.handle.net/10230/58497
dc.description.abstract Background. NGS-based genetic diagnosis has completely revolutionized the human genetics field. In this study, we have aimed to identify new genes and mutations by Whole Exome Sequencing (WES) responsible for inherited retinal dystrophies (IRD). Methods. A cohort of 33 pedigrees affected with a variety of retinal disorders was analysed by WES. Initial prioritization analysis included around 300 IRD-associated genes. In non-diagnosed families a search for pathogenic mutations in novel genes was undertaken. Results. Genetic diagnosis was attained in 18 families. Moreover, a plausible candidate is proposed for 10 more cases. Two thirds of the mutations were novel, including 4 chromosomal rearrangements, which expand the IRD allelic heterogeneity and highlight the contribution of private mutations. Our results prompted clinical re-evaluation of some patients resulting in assignment to a syndromic instead of non-syndromic IRD. Notably, WES unveiled four new candidates for non-syndromic IRD: SEMA6B, CEP78, CEP250, SCLT1, the two latter previously associated to syndromic disorders. We provide functional data supporting that missense mutations in CEP250 alter cilia formation. Conclusion. The diagnostic efficiency of WES, and strictly following the ACMG/AMP criteria is 55% in reported causative genes or functionally supported new candidates, plus 30% families in which likely pathogenic or VGUS/VUS variants were identified in plausible candidates. Our results highlight the clinical utility of WES for molecular diagnosis of IRD, provide a wider spectrum of mutations and concomitant genetic variants, and challenge our view on syndromic vs non-syndromic, and causative vs modifier genes.
dc.description.sponsorship This study was supported by grants SAF2013-49069-C2-1-R (Ministerio de Economía y Competitividad), 2014SGR-0932 (Generalitat de Catalunya), and La Marató TV3 (Project Marató 201417-30-31-32) to G.M. and R. G-D and PT13/0001/0044 (Ministerio de Economía y Competitividad) to R.T. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher Public Library of Science (PLoS)
dc.relation.ispartof PLoS ONE. 2016 Dec 22;11(12):e0168966
dc.rights © 2016 de Castro-Miró 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 credited.
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.subject.other Mutació (Biologia)
dc.subject.other Genètica humana
dc.subject.other Cromosomes humans
dc.title Novel candidate genes and a wide spectrum of structural and point mutations responsible for inherited retinal dystrophies revealed by exome sequencing
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1371/journal.pone.0168966
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2013-49069-C2-1-R
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion

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