Inherited retinal diseases in Kentucky: diagnostic yield, gene variants, and novel mutations in a U.S. population

Inherited retinal diseases (IRDs) are a group of heterogeneous conditions leading to visual impairment and blindness with over 280 associated genes identified so far. This study aims to provide an initial characterization of the clinical and genetic landscape of IRDs in the United States with a cohort from Kentucky and contribute to the existing knowledge from studies in other regions. This single-academic center retrospective analysis was conducted on patients seen at the University of Kentucky Ophthalmic Genetic Services from January 2019 to March 2022 with a diagnosis of or concern for unspecified IRD and who underwent subsequent genetic testing with an IRD panel. The study included 366 subjects with a pre-genetic testing IRD diagnosis, with an age range from 9 to 87 years old and mean age of 42.11 years. The most common pre-genetic diagnoses were retinitis pigmentosa (RP) in 116 subjects (31.69%), referral for ‘concern for unspecified IRD’ in 107 subjects (29.23%), and macular dystrophy in 31 subjects (8.46%). The diagnostic yield of genetic testing for rod-cone dystrophy (RCD) cases was 83.89%. The five most common genetic testing confirmed diagnoses were RP, Usher syndrome type 2 (USH2A), Stargardt disease (STGD), Bardet-Biedl syndrome (BBS), and Usher syndrome type 1 (USH1). A total of 46 individual genes had pathogenic variants. The three most frequently pathogenic genes were RHO, USH2A, and ABCA4, with 5 pathogenic variants within RHO, 20 within USH2A, and 17 within ABCA4. Five novel variants were identified across the WFS1, ARSG, USH2A, ADGRV1, and PCDH15 genes. This study characterizes the genetic landscape of IRDs in a Kentucky cohort, with pathogenic variants in 46 genes, including five novel variants. These novel variants highlight the need for continued research to identify more population-specific variants. The findings highlight the value of genetic testing and contribute to advancing IRD research and care. ClinicalTrials.gov registration number: NCT06177977. First posted date: 12/20/2023.