Many inherited eye disease genes rarely cause vision loss, study found

Many genetic variants linked to inherited eye disorders rarely lead to disease, meaning up to 2% of people could carry these variants without ever developing vision problems, according to a new study published on January 8, 2026, in the American Society of Human Genetics.

Inherited retinal degenerations (IRD), better known as inherited retinal eye diseases, are a leading cause of blindness among working-age adults, according to study authors. For years, these conditions were thought to be caused by single genes that almost always lead to disease when a harmful variant is present.

Examples of these diseases shared by Duke Ophthalmology include:

1. Retinitis Pigmentosa - Retinal cells that sense light gradually die, eventually leading to significant vision loss. A common early symptom, which usually occurs in childhood, is the inability to see at night or in low light, followed by loss of peripheral vision.
2. Leber Congenital Amaurosis - Severe vision problems occur as early as infancy. Children may be extremely farsighted and have crossed eyes or eyes that are constantly in motion because of their inability to focus.
3. Stargardt Disease - Damage to the macula, which is the part of the retina that provides straight-ahead vision, causes central vision loss. Symptoms usually occur during childhood, but the disease might not be detected until adulthood because it progresses gradually.

The belief that these conditions were caused by a single gene that leads to disease has shaped how genetic testing is used in clinics and how researchers look for new treatments. However, most past research focused on patients who already had symptoms and were seen in specialty eye clinics, which may give an unclear picture of how these genes behave in the broader population.

Researchers from the University of British Columbia and the Ocular Genomics Institute at Massachusetts Eye and Ear and Harvard Medical School sought to understand how often IRD-linked genetic variants actually lead to vision loss. They analyzed genetic, medical record and eye imaging data from hundreds of thousands of participants in large biobanks, including the All of Us Research Program and the UK Biobank.

Using genetic databases, the team identified IRD-associated genes and manually reviewed pathogenic or loss-of-function variants to confirm inheritance patterns and reduce errors. To estimate disease risk, they grouped diagnosis codes from strict IRD definitions to broader eye-related conditions and calculated how often participants carried these diagnoses.

Lastly, retinal imaging and statistical analyses were used to validate findings and assess whether factors such as age, smoking history, education level or other health conditions influenced disease risk.

Researchers found 481 people with definite IRD-linked gene variants out of 317,964 All of Us participants with genetic and health record data. Most had variants in autosomal dominant genes, followed by X-linked and autosomal recessive genes, representing 167 different variants in 33 genes.

Based on disease codes, frequencies ranged from 9.4% for the strict set to 28.1% for the broadest set, showing most carriers do not develop disease. The most common genes were PRPH2, CRX, RHO, RPGR, BEST1 and RP1, though penetrance varied.

Some variants were linked to other eye conditions such as age-related macular degeneration and cystoid macular edema. Retinal imaging from the UK Biobank confirmed low penetrance, with 16.1%–27.9% showing abnormalities. It was also found that age slightly increased disease, but even people over 60 rarely had vision problems.

Strengths from this study include the large biobanks that link genetic information with medical records, the carefully checked IRD-related gene variants and confirmation with eye imaging from a separate group. These steps helped show how often IRD-linked genes actually cause disease and showed that health record codes can reliably identify affected people.

The study’s limitations include data from biobanks that may recruit healthier or wealthier participants; also, some rare gene variants were not found in all datasets. Lastly, authors noted that eye imaging only covered part of the retina.

Authors concluded that low penetrance is common for these genes, meaning extra genetic or environmental factors are needed to cause disease. They suggest being careful with genetic testing for those without symptoms and recommend studying what affects penetrance and disease severity.