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Title: Novel candidate genes and a wide spetrum of structural and point mutations responsible for inherited retinal dystrophies revealed by exome sequencing
Author: Castro Miró, Marta de
Tonda, Raul
Escudero Ferruz, Paula
Andrés, Rosa
Mayor Lorenzo, Andres
Castro, Joaquín
Ciccioli, Marcela
Hidalgo, Daniel A.
Rodríguez Ezcurra, Juan José
Farrando, Jorge
Pérez Santonja, Juan J.
Cormand Rifà, Bru
Marfany i Nadal, Gemma
Gonzàlez-Duarte, Roser
Keywords: Genètica humana
Mutació (Biologia)
Human genetics
Mutation (Biology)
Issue Date: 22-Dec-2016
Publisher: Public Library of Science (PLoS)
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.
Note: Reproducció del document publicat a:
It is part of: PLoS One, 2016, vol. 11, num. 12, p. e0168966
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ISSN: 1932-6203
Appears in Collections:Articles publicats en revistes (Genètica, Microbiologia i Estadística)

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