2. Academic Validation
  3. Novel Candidate Genes and a Wide Spectrum of Structural and Point Mutations Responsible for Inherited Retinal Dystrophies Revealed by Exome Sequencing

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.
Marta de Castro-Miró 1 2 3,  Raul Tonda 4 5,  Paula Escudero-Ferruz 1,  Rosa Andrés 1 2,  Andrés Mayor-Lorenzo 6,  Joaquín Castro 7,  Marcela Ciccioli 8,  Daniel A Hidalgo 9,  Juan José Rodríguez-Ezcurra 10,  Jorge Farrando 11,  Juan J Pérez-Santonja 12,  Bru Cormand 1 2 3,  Gemma Marfany 1 2 3,  Roser Gonzàlez-Duarte 1 2 3
Affiliations

Affiliations

  • 1 Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.
  • 2 Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Barcelona, Spain.
  • 3 Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, Spain.
  • 4 CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
  • 5 Universitat Pompeu Fabra (UPF), Barcelona, Spain.
  • 6 Asociación EsRetina Asturias, Oviedo, Asturias, Spain.
  • 7 Servicio de Oftalmología, Unidad de Retina, Hospital Universitario Central de Asturias, Oviedo, Spain.
  • 8 Stargardt APNES-Retina, Buenos Aires, Argentina.
  • 9 Hospital Interzonal General de Agudos Eva Perón, Buenos Aires, Argentina.
  • 10 Barraquer - Centro de Oftalmología Barcelona, Barcelona, Spain.
  • 11 Institut Oftalmològic Quirón Barcelona, Barcelona, Spain.
  • 12 Department of Ophthalmology, Alicante University General Hospital, Alicante Institute for Health and Biomedical Research (ISABIAL-FISABIO Foundation), Alicante, Spain.
PMID: 28005958 DOI: 10.1371/journal.pone.0168966
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.

Figures