Abstract
Inherited retinopathies affect approximately two and a half million people globally, yet the majority of affected patients lack clear genetic diagnoses given the diverse range of genes and mutations implicated in these conditions. We present results from a next-generation sequencing study of a large inherited retinal disease patient population, with the goal of providing clear and actionable genetic diagnoses. Targeted sequencing was performed on 539 individuals from 309 inherited retinal disease pedigrees. Causative mutations were identified in the majority (57%, 176/309) of pedigrees. We report the association of many previously unreported variants with retinal disease, as well as new disease phenotypes associated with known genes, including the first association of the SLC24A1 gene with retinitis pigmentosa. Population statistics reporting the genes most commonly implicated in retinal disease in the cohort are presented, as are some diagnostic conundrums that can arise during such studies. Inherited retinal diseases represent an exemplar group of disorders for the application of panel-based next-generation sequencing as an effective tool for detection of causative mutations.
Highlights
Inherited retinal disorders (IRDs) comprise a broad spectrum of genetically heterogeneous conditions with overlapping clinical presentations
Many novel and previously reported mutations were identified in this IRD cohort, as were new ocular disease phenotypes associated with genes previously implicated in other retinal disorders
Patients over 18 years with an IRD were eligible to enrol in the study
Summary
Inherited retinal disorders (IRDs) comprise a broad spectrum of genetically heterogeneous conditions with overlapping clinical presentations. Mutations in over 200 genes have been implicated in inherited retinal disorders as a whole to date[3], with the result that traditional sequencing approaches are usually inadequate for the task of identifying causative mutations. NGS technology has advanced at an exponential pace, with the cost per megabase of sequence halving regularly[4,5] This has enabled enhanced diagnosis for both genetic and infectious diseases[6], as well as providing insights into mutations driving tumorigenesis. We present results from the Target 5000 project, a NGS study aimed at identifying causative mutations in an extensive Irish IRD patient cohort. Many novel and previously reported mutations were identified in this IRD cohort, as were new ocular disease phenotypes associated with genes previously implicated in other retinal disorders
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