title: Improving the management of Inherited Retinal Dystrophies by targeted sequencing of a population-specific gene panel.
abstract: Next-generation sequencing (NGS) has overcome important limitations to the molecular diagnosis of Inherited Retinal Dystrophies (IRD) such as the high clinical and genetic heterogeneity and the overlapping phenotypes. The purpose of this study was the identification of the genetic defect in 32 Spanish families with different forms of IRD. With that aim, we implemented a custom NGS panel comprising 64 IRD-associated genes in our population, and three disease-associated intronic regions. A total of 37 pathogenic mutations (14 novels) were found in 73% of IRD patients ranging from 50% for autosomal dominant cases, 75% for syndromic cases, 83% for autosomal recessive cases, and 100% for X-linked cases. Additionally, unexpected phenotype-genotype correlations were found in 6 probands, which led to the refinement of their clinical diagnoses. Furthermore, intra- and interfamilial phenotypic variability was observed in two cases. Moreover, two cases unsuccessfully analysed by exome sequencing were resolved by applying this panel. Our results demonstrate that this hypothesis-free approach based on frequently mutated, population-specific loci is highly cost-efficient for the routine diagnosis of this heterogeneous condition and allows the unbiased analysis of a miscellaneous cohort. The molecular information found here has aid clinical diagnosis and has improved genetic counselling and patient management.
authors.affiliation: Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville, University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain.|Centre for Biomedical Network Research on Rare Diseases (CIBERER), Spain.
authors.forename: Nereida
authors.initials: N
authors.lastname: Bravo-Gil
authors.affiliation: Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville, University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain.|Centre for Biomedical Network Research on Rare Diseases (CIBERER), Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Méndez-Vidal
authors.affiliation: Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville, University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Romero-Pérez
authors.affiliation: Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville, University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain.|Centre for Biomedical Network Research on Rare Diseases (CIBERER), Spain.
authors.forename: María
authors.initials: M
authors.lastname: González-del Pozo
authors.affiliation: Department of Ophthalmology, University Hospital Virgen Macarena, Seville, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Rodríguez-de la Rúa
authors.affiliation: Centre for Biomedical Network Research on Rare Diseases (CIBERER), Spain.|Computational Genomics Department, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain.|Functional Genomics Node, (INB) at CIPF, Valencia, Spain.
authors.forename: Joaquín
authors.initials: J
authors.lastname: Dopazo
authors.affiliation: Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville, University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain.|Centre for Biomedical Network Research on Rare Diseases (CIBERER), Spain.
authors.forename: Salud
authors.initials: S
authors.lastname: Borrego
authors.affiliation: Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville, University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain.|Centre for Biomedical Network Research on Rare Diseases (CIBERER), Spain.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Antiñolo
mesh_terms: D000483:Alleles; D003198:Computer Simulation; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D005136:Eye Proteins / Q000235:genetics; D015723:Gene Library; D056726:Genetic Association Studies; D018740:Genetic Heterogeneity; D015316:Genetic Therapy / Q000379:methods*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009154:Mutation; D010641:Phenotype; D058499:Retinal Dystrophies / Q000235:genetics / Q000628:therapy*
chemical_list: D005136:Eye Proteins