Population Penetrance of Inherited Retinal Degeneration-Linked Genotypes Lower Than Expected

MONDAY, Dec. 29 2025 (HealthDay News) -- Population-level penetrance of inherited retinal degeneration (IRD)-associated genotypes is lower than traditionally assumed, while IRD genotypes are more prevalent than expected, according to a study published online Dec. 22 in the American Journal of Human Genetics.Kirill Zaslavsky, M.D., Ph.D., from the University of British Columbia in Vancouver, Canada, and colleagues used large biobanks with linked genomic and clinical data to quantify the population-level penetrance of IRD-associated variants. A cohort with definite IRD-compatible genotypes was curated by screening 317,964 All of Us (AoU) participants for loss-of-function or pathogenic IRD variants. To derive lower- and upper-bound penetrance estimates via disease annotation frequencies (DAFs), three nested International Classification of Diseases-9/10 code sets ("IRD," "retinopathy," and "screening") were defined.The researchers found that DAFs ranged from 9.4 to 28.1 percent for IRD and screening, respectively, within a cohort of 481 AoU participants with definite IRD-compatible genotypes; these were enriched relative to the prevalence of the code sets in AoU. Retinal imaging of U.K. Biobank participants who shared variants with the AoU cohort were examined for validation. Overall, 16.1 to 27.9 percent of participants with shared variants in the U.K. Biobank exhibited definite or possible IRD features, concordant with AoU estimates. Penetrance was not predicted by participant demographics, smoking, socioeconomic status, or comorbidities. The researchers note the findings suggest that IRD genotypes are more prevalent (0.7 to 2.1 percent) than expected."The large number of individuals that do not develop an IRD despite having a compatible genotype provide an opportunity to design well-powered research studies to discover disease modifiers, which could spur development of novel therapies," Zaslavsky said in a statement.Abstract/Full Text.Sign up for our weekly HealthDay newsletter