Abstract
Inherited retinal diseases (IRD) are a heterogeneous group of diseases that mainly affect the retina; more than 250 genes have been linked to the disease and more than 20 different clinical phenotypes have been described. This heterogeneity both at the clinical and genetic levels complicates the identification of causative mutations. Therefore, a detailed genetic characterization is important for genetic counselling and decisions regarding treatment. In this study, we developed a method consisting on pooled targeted next generation sequencing (NGS) that we applied to 316 eye disease related genes, followed by High Resolution Melting and copy number variation analysis. DNA from 115 unrelated test samples was pooled and samples with known mutations were used as positive controls to assess the sensitivity of our approach. Causal mutations for IRDs were found in 36 patients achieving a detection rate of 31.3%. Overall, 49 likely causative mutations were identified in characterized patients, 14 of which were first described in this study (28.6%). Our study shows that this new approach is a cost-effective tool for detection of causative mutations in patients with inherited retinopathies.
Highlights
Inherited retinal diseases (IRD) are a heterogeneous group of diseases that mainly affect the retina; more than 250 genes have been linked to the disease and more than 20 different clinical phenotypes have been described
In order to simplify the sequencing process and to reduce the costs associated with individual labelling of DNA samples, we have developed a mutation detection approach based on targeted next generation sequencing (NGS) in combination with high resolution melting (HRM) analysis
We have developed a cost-effective method for the diagnosis of IRDs based on pooled genomic DNA targeted NGS, in combination with HRM as a highly sensitive, versatile and affordable genotyping method
Summary
Inherited retinal diseases (IRD) are a heterogeneous group of diseases that mainly affect the retina; more than 250 genes have been linked to the disease and more than 20 different clinical phenotypes have been described. This heterogeneity both at the clinical and genetic levels complicates the identification of causative mutations. A more practical approach for clinical diagnosis may consist of an initial genetic screening of a subset of genes associated with a phenotype using targeted NGS, followed by a second more extensive genome analysis, such as WES6, and the analysis of the copy number variations (CNVs)[1], for challenging cases for which the first strategy fails to indicate any genetic explanation
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