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Improving the management of Inherited Retinal Dystrophies by targeted sequencing of a population-specific gene panel.

By Nereida Bravo-Gil, Cristina Méndez-Vidal, Laura Romero-Pérez, María González-Del Pozo, Enrique Rodríguez-de la Rúa, Joaquín Dopazo, Salud Borrego and Guillermo Antiñolo

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.This work was supported by the Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Economy and Competitiveness, Spain (PI11-02923), CIBERER ACCI, CDTI FEDER-Innterconecta (EXP00052887/ITC-20111037), Regional Ministry of Economy, Innovation, Science and Employment of the Autonomous Government of Andalusia (CTS-1664) and the Foundation Ramon Areces (CIVP16A1856). The CIBERER is an initiative of the ISCIII, Spanish Ministry of Economy and Competitiveness. NB-G is supported by fellowship FI12/00545 from ISCIII.Ye

Topics: Exoma, Estudios de asociación genética, Asesoramiento genético, Heterogeneidad genética, Genotipo, Fenotipo, Distrofias retinianas, Medical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Exome, Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Genetic Association Studies, Medical Subject Headings::Disciplines and Occupations::Natural Science Disciplines::Biological Science Disciplines::Biology::Genetics::Genetics, Medical::Genetic Counseling, Medical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Variation::Genetic Heterogeneity, Medical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genotype, Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Sequence Analysis::High-Throughput Nucleotide Sequencing, Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans, Medical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Variation::Mutation, Medical Subject Headings::Phenomena and Processes::Genetic Phenomena::Phenotype, Medical Subject Headings::Diseases::Eye Diseases::Retinal Diseases::Retinal Degeneration::Retinal Dystrophies
Publisher: 'Springer Science and Business Media LLC'
Year: 2016
DOI identifier: 10.1038/srep23910
OAI identifier: oai:oai:www.repositoriosalud.es:10668:10668/2265
Provided by: Fondo Bibliográfico Digital Institucional
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