Diagnostic Contribution of Genes with Treatments or Interventional Clinical Trials in a Large Retinal Dystrophy Cohort

Abstract

Purpose : In the recent past, vision loss secondary to inherited retinal disease (IRD) was considered ‘incurable.’ Progress in both gene therapy and the molecular characterization of IRDs has led to a rapid increase in the number of gene-specific treatments as well as planned and ongoing interventional clinical trials for ocular disease. Perhaps less apparent is how diagnostic genetic testing, such as with next-generation sequencing (NGS), informs the opportunity for gene-specific treatments and interventional clinical trials for IRD. Here, we assess how NGS-based panel results impact access to targeted treatment and clinical trials in a large cohort of patients with IRD.

Methods : We carried out a retrospective analysis of test results from 18,026 deidentified patients who were tested consecutively with an IRD-related panel at Blueprint Genetics (Table 1). The target regions included coding exons, intronic regions ± 20 bps from the exon-intron boundaries and clinically significant noncoding variants. Copy number analysis was done bioinformatically from the NGS data using 2 different pipelines, including 1 proprietary pipeline developed for the detection of small, exon-level CNVs. Variant interpretation was performed according to American College of Medical Genetics guidelines. Clinical information, demographics, and results were extracted from the internal laboratory database.

Results : The median coverage of all target regions was 99.91% at >20X while the median sequencing depth was 210X. The median age at testing was 46 years. Males made up 48.4% (8,730) of the cohort while females made up 51.1% (9,203). Sex was not specified in 0.5% (93) patients. A molecular diagnosis was made in 9,156 (50.8%) patients while a variant of unknown significance (VUS) favoring pathogenic was identified in an additional 973 (5.4%) patients. A total of 214 genes were involved in the molecular diagnoses of IRD. In particular, diagnoses involving the 14 genes for which therapy or clinical trial is available accounted for 41.7% of the total diagnoses (Table 2).

Conclusions : For every 5 patients who received a molecular diagnosis for their IRD in this cohort, 2 have a diagnosis involving a gene/specific variant that may allow them to access treatment or a clinical trial.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.