A recent study by researchers at Mass General Brigham has found that genetic variants previously believed to always cause inherited retinal degenerations (IRDs) result in disease far less frequently than expected. The research, published in The American Journal of Human Genetics, used data from large public biobanks to show that these genes led to IRDs in fewer than 30% of cases.
For many years, the prevailing belief in genetics has been that rare inherited disorders—often called Mendelian diseases—are caused by mutations in single critical genes. This understanding was based on studies involving patients and families already affected by such conditions, including IRDs, which are a leading cause of legal blindness among working adults.
"Our study indicates that the number of people in the general population with genetic variants linked to inherited retinal disorders is much higher than previously thought, and population penetrance of these genes is markedly lower than traditionally assumed," said Eric Pierce, MD, PhD, director of Ocular Genomics Institute at Mass Eye and Ear and Chatlos Professor of Ophthalmology at Harvard Medical School. "These findings are striking and suggest that the traditional paradigm of Mendelian diseases needs to be updated."
The researchers noted that previous estimates may have been inflated due to ascertainment bias—a tendency for clinical studies to focus on individuals who already exhibit symptoms or come from affected families. By using large volunteer biobanks such as the National Institutes of Health's All of Us Research Program (AoU) and the UK Biobank (UKB), they were able to take a more unbiased approach.
The team curated a list of 167 pathogenic variants across 33 genes known to be associated with IRDs. Screening nearly 318,000 AoU participants revealed 481 individuals with genotypes compatible with IRD. However, only 9.4% had an IRD diagnosis when strict diagnostic codes were applied; this figure rose to just 28.1% when broader criteria were used.
To confirm their results, researchers examined data from the UK Biobank, which includes retinal images for about 100,000 participants. Among those carrying IRD-associated variants, between 16.1% and 27.9% showed evidence or possible signs of IRD—findings consistent with those from the AoU dataset. Factors such as demographics or comorbidities did not predict whether someone would develop disease.
The study suggests that additional genetic or environmental factors may influence whether these gene variants actually lead to disease. This new perspective could affect how genetic testing is interpreted in clinical settings and guide future development of treatments for IRDs and other rare genetic disorders.
