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

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 Spani...

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Autores principales: Bravo-Gil, Nereida, Méndez-Vidal, Cristina, Romero-Pérez, Laura, González-del Pozo, María, Rodríguez-de la Rúa, Enrique, Dopazo, Joaquín, Borrego, Salud, Antiñolo, Guillermo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4817143/
https://www.ncbi.nlm.nih.gov/pubmed/27032803
http://dx.doi.org/10.1038/srep23910
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author Bravo-Gil, Nereida
Méndez-Vidal, Cristina
Romero-Pérez, Laura
González-del Pozo, María
Rodríguez-de la Rúa, Enrique
Dopazo, Joaquín
Borrego, Salud
Antiñolo, Guillermo
author_facet Bravo-Gil, Nereida
Méndez-Vidal, Cristina
Romero-Pérez, Laura
González-del Pozo, María
Rodríguez-de la Rúa, Enrique
Dopazo, Joaquín
Borrego, Salud
Antiñolo, Guillermo
author_sort Bravo-Gil, Nereida
collection PubMed
description 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.
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spelling pubmed-48171432016-04-05 Improving the management of Inherited Retinal Dystrophies by targeted sequencing of a population-specific gene panel Bravo-Gil, Nereida Méndez-Vidal, Cristina Romero-Pérez, Laura González-del Pozo, María Rodríguez-de la Rúa, Enrique Dopazo, Joaquín Borrego, Salud Antiñolo, Guillermo Sci Rep Article 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. Nature Publishing Group 2016-04-01 /pmc/articles/PMC4817143/ /pubmed/27032803 http://dx.doi.org/10.1038/srep23910 Text en Copyright © 2016, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Bravo-Gil, Nereida
Méndez-Vidal, Cristina
Romero-Pérez, Laura
González-del Pozo, María
Rodríguez-de la Rúa, Enrique
Dopazo, Joaquín
Borrego, Salud
Antiñolo, Guillermo
Improving the management of Inherited Retinal Dystrophies by targeted sequencing of a population-specific gene panel
title Improving the management of Inherited Retinal Dystrophies by targeted sequencing of a population-specific gene panel
title_full Improving the management of Inherited Retinal Dystrophies by targeted sequencing of a population-specific gene panel
title_fullStr Improving the management of Inherited Retinal Dystrophies by targeted sequencing of a population-specific gene panel
title_full_unstemmed Improving the management of Inherited Retinal Dystrophies by targeted sequencing of a population-specific gene panel
title_short Improving the management of Inherited Retinal Dystrophies by targeted sequencing of a population-specific gene panel
title_sort improving the management of inherited retinal dystrophies by targeted sequencing of a population-specific gene panel
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4817143/
https://www.ncbi.nlm.nih.gov/pubmed/27032803
http://dx.doi.org/10.1038/srep23910
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