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.