title: Targeted Next-Generation Sequencing Improves the Diagnosis of Autosomal Dominant Retinitis Pigmentosa in Spanish Patients.
abstract: OBJECTIVE
  Next-generation sequencing (NGS) has been demonstrated to be an effective strategy for the detection of mutations in retinal dystrophies, a group of inherited diseases that are highly heterogeneous. Therefore, the aim of this study is the application of an NGS-based approach in a Spanish cohort of autosomal dominant retinitis pigmentosa (RP) patients to find out causative mutations.
  
  
  METHODS
  Index cases of 59 Spanish families with initial diagnosis of autosomal dominant RP and unsuccessfully studied for mutations in the most common RP causal genes, were selected for application of a NGS-based approach with a custom panel for 73 genes related to retinal dystrophies. Candidate variants were select based on frequency, pathogenicity, inherited model, and phenotype. Subsequently, confirmation by Sanger sequencing, cosegregation analysis, and population studies, was applied for determining the implication of those variants in the pathology.
  
  
  RESULTS
  Overall 31 candidate variants were selected. From them, 17 variants were considered as mutations causative of the disease, 64% (11/17) of them were novel and 36% (6/17) were known RP-related mutations. Therefore, applying this technology16 families were characterized rendering a mutation detection rate of 27% (16/59). Of them, 5% (3/59) of cases displayed mutations in recessive or X-linked genes (ABCA4, RPGR, and RP2) allowing a genetic and clinical reclassification of those families. Furthermore, seven novel variants with uncertain significance and seven novel variants probably not causative of disease were also found.
  
  
  CONCLUSIONS
  This NGS strategy is a fast, effective, and reliable tool to detect known and novel mutations in autosomal dominant RP patients allowing genetic reclassification in some cases and increasing the knowledge of pathogenesis in retinal dystrophies.
authors.affiliation: Department of Genetics, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz University Hospital (IIS-FJD, UAM), Madrid, Spain 2Center of Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Fernandez-San Jose
authors.affiliation: Department of Genetics, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz University Hospital (IIS-FJD, UAM), Madrid, Spain 2Center of Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Corton
authors.affiliation: Department of Genetics, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz University Hospital (IIS-FJD, UAM), Madrid, Spain 2Center of Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.
authors.forename: Fiona
authors.initials: F
authors.lastname: Blanco-Kelly
authors.affiliation: Department of Genetics, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz University Hospital (IIS-FJD, UAM), Madrid, Spain 2Center of Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.
authors.forename: Almudena
authors.initials: A
authors.lastname: Avila-Fernandez
authors.affiliation: Department of Genetics, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz University Hospital (IIS-FJD, UAM), Madrid, Spain 2Center of Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Lopez-Martinez
authors.affiliation: Department of Genetics, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz University Hospital (IIS-FJD, UAM), Madrid, Spain 2Center of Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.
authors.forename: Iker
authors.initials: I
authors.lastname: Sanchez-Navarro
authors.affiliation: Department of Genetics, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz University Hospital (IIS-FJD, UAM), Madrid, Spain 2Center of Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.
authors.forename: Rocio
authors.initials: R
authors.lastname: Sanchez-Alcudia
authors.affiliation: Department of Genetics, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz University Hospital (IIS-FJD, UAM), Madrid, Spain 2Center of Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Perez-Carro
authors.affiliation: Department of Genetics, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz University Hospital (IIS-FJD, UAM), Madrid, Spain 2Center of Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.
authors.forename: Olga
authors.initials: O
authors.lastname: Zurita
authors.affiliation: Department of Genetics, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz University Hospital (IIS-FJD, UAM), Madrid, Spain.
authors.forename: Noelia
authors.initials: N
authors.lastname: Sanchez-Bolivar
authors.affiliation: Center of Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain 3Department of Ophthalmology, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz University Hospital (IIS-FJD, UAM), Madrid, Spain.
authors.forename: Maria Isabel
authors.initials: MI
authors.lastname: Lopez-Molina
authors.affiliation: Center of Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain 3Department of Ophthalmology, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz University Hospital (IIS-FJD, UAM), Madrid, Spain.
authors.forename: Blanca
authors.initials: B
authors.lastname: Garcia-Sandoval
authors.affiliation: Department of Genetics, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz University Hospital (IIS-FJD, UAM), Madrid, Spain 2Center of Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Riveiro-Alvarez
authors.affiliation: Department of Genetics, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz University Hospital (IIS-FJD, UAM), Madrid, Spain 2Center of Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Ayuso
mesh_terms: D004247:DNA / Q000235:genetics*; D005260:Female; D050172:Genes, X-Linked / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D015994:Incidence; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D012174:Retinitis Pigmentosa / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D013030:Spain / Q000453:epidemiology
chemical_list: D004247:DNA