Inherited retinal disease mutations are less likely to actually cause disease than previously expected, according to research led by Harvard University.
The study, published in the American Journal of Human Genetics, looked at people in both the All of Us cohort in the U.S. and the UK Biobank and showed that less than 30% of people carrying known inherited retinal degeneration mutations actually had signs of disease despite correcting for factors such as age and misclassification.
The researchers suggest that background genetic factors, epigenetics, or environmental exposures likely explain whether and how severely carriers are affected.
“Although variants in over 80% of inherited retinal degeneration-associated genes are believed to have complete or near-complete penetrance, the main mechanism driving gene discovery to date has been genetic testing of patients with shared phenotypes, referred to specialty clinics,” write the authors.
“This approach introduces a phenotypic ascertainment bias, which can inflate estimates of disease penetrance and severity, fail to capture the full phenotypic spectrum, and increase the risk of spurious genotype-phenotype associations.”
In this study, co-lead author Eric Pierce, MD, PhD, a professor of ophthalmology at Harvard Medical School, and team screened 317,964 adults in the All of Us biobank for 167 pathogenic variants in 33 genes and found 481 people carrying known retinal disease variants.
Using strict diagnostic codes from medical records, the researchers found that only 9.4% of people with these genetic changes had an inherited retinal disease diagnosis. When they used a broader set of eye‑related diagnosis codes, only 28.1% of people with the genetic changes had the expected disease.
The authors also validated their findings in the UK Biobank. Overall, 482 people carried 43 of the selected retinal disease variants, and 68 had retinal images that were actually reviewed for signs of disease. Similar to the findings in All of Us, 16–28% of carriers in the UK Biobank sample actually had signs of retinal disease.
“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 Pierce in a press statement.
“These findings are striking and suggest that the traditional paradigm of Mendelian diseases needs to be updated.”
