title: Novel Candidate Genes and a Wide Spectrum of Structural and Point Mutations Responsible for Inherited Retinal Dystrophies Revealed by Exome Sequencing.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Barcelona, Spain.|Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: de Castro-Miró
authors.affiliation: CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.|Universitat Pompeu Fabra (UPF), Barcelona, Spain.
authors.forename: Raul
authors.initials: R
authors.lastname: Tonda
authors.affiliation: Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Paula
authors.initials: P
authors.lastname: Escudero-Ferruz
authors.affiliation: Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Barcelona, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Andrés
authors.affiliation: Asociación EsRetina Asturias, Oviedo, Asturias, Spain.
authors.forename: Andrés
authors.initials: A
authors.lastname: Mayor-Lorenzo
authors.affiliation: Servicio de Oftalmología, Unidad de Retina, Hospital Universitario Central de Asturias, Oviedo, Spain.
authors.forename: Joaquín
authors.initials: J
authors.lastname: Castro
authors.affiliation: Stargardt APNES-Retina, Buenos Aires, Argentina.
authors.forename: Marcela
authors.initials: M
authors.lastname: Ciccioli
authors.affiliation: Hospital Interzonal General de Agudos Eva Perón, Buenos Aires, Argentina.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Hidalgo
authors.affiliation: Barraquer - Centro de Oftalmología Barcelona, Barcelona, Spain.
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Rodríguez-Ezcurra
authors.affiliation: Institut Oftalmològic Quirón Barcelona, Barcelona, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Farrando
authors.affiliation: Department of Ophthalmology, Alicante University General Hospital, Alicante Institute for Health and Biomedical Research (ISABIAL-FISABIO Foundation), Alicante, Spain.
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Pérez-Santonja
authors.affiliation: Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Barcelona, Spain.|Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, Spain.
authors.forename: Bru
authors.initials: B
authors.lastname: Cormand
authors.affiliation: Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Barcelona, Spain.|Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, Spain.
authors.forename: Gemma
authors.initials: G
authors.lastname: Marfany
authors.affiliation: Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Barcelona, Spain.|Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, Spain.
authors.forename: Roser
authors.identifier: http://orcid.org/0000-0003-0093-923X
authors.initials: R
authors.lastname: Gonzàlez-Duarte
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000502:physiology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology; D002869:Chromosome Aberrations; D015331:Cohort Studies; D059472:Exome; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010375:Pedigree; D017354:Point Mutation; D058499:Retinal Dystrophies / Q000235:genetics*; D039961:Semaphorins / Q000235:genetics / Q000502:physiology; D017422:Sequence Analysis, DNA; D015222:Sodium Channels / Q000235:genetics / Q000502:physiology
chemical_list: D001324:Autoantigens; C000618001:CEP78 protein, human; D018797:Cell Cycle Proteins; C111329:CEP250 protein, human; C000590031:SCLT1 protein, human; C504081:SEMA6B protein, human; D039961:Semaphorins; D015222:Sodium Channels