Why this study matters for people with Best disease-like findings

Best vitelliform macular dystrophy, often called Best disease, is classically associated with changes in the BEST1 gene. Yet a yellow, egg-yolk-like lesion in the macula—the central area of the retina responsible for detailed vision—can also occur in other inherited retinal diseases. This study highlights IMPG2 as one such gene and shows why genetic testing can be especially important for people and families diagnosed with adult-onset vitelliform macular dystrophy or a Best disease-like retinal appearance.

IMPG2-associated retinopathy can look quite different from person to person. Some individuals develop vitelliform macular changes, while others have retinitis pigmentosa or subtler, multifocal abnormalities affecting photoreceptors. Identifying the causative gene helps clarify the diagnosis, informs family counseling, and may become increasingly important as gene-targeted therapies are developed.

A Korean multicenter view of IMPG2-associated retinopathy

Researchers reviewed 14 people from four institutions in Korea who had genetically confirmed IMPG2-associated retinopathy. The group included 11 men and three women, with an average age of about 41 years. Thirteen of the 14 participants had disease in both eyes.

The clinical range was striking:

  • Seven patients had adult-onset vitelliform macular dystrophy.
  • Six patients had retinitis pigmentosa.
  • One patient had an atypical macular dystrophy, with subtle and multifocal changes in the photoreceptors.

This range reinforces an important point: a gene does not always produce one fixed clinical picture. In particular, an adult with vitelliform changes may have a condition that resembles Best disease on retinal examination but is caused by a different gene and may have different implications for inheritance and disease course.

The study assessed visual acuity, retinal appearance, and optical coherence tomography (OCT), a noninvasive scan that provides cross-sectional images of retinal layers. Genetic testing was performed using inherited-retinal-disease gene panels or whole-exome sequencing, and variants were classified using established ACMG criteria.

Splice-site variants were the major genetic finding

The most notable result was the high frequency of variants affecting RNA splicing. Splicing is the cellular process that edits an initial RNA copy of a gene into the final instructions used to make a protein. Variants at splice sites can disrupt this editing process, potentially resulting in an abnormal or absent protein.

Twelve of the 14 patients—85.7%—had variants clustered near a small region of the IMPG2 gene, around the junction between exons 7 and 8 or at the splice acceptor site of exon 9. The most frequent variant, c.828+1G>A, was identified in eight participants, or 57.1% of the cohort. Two additional splice-related variants, c.829-2_829-1delAG and c.909-2A>T, were also found.

The concentration of variants in this region may indicate a founder effect, in which a genetic variant becomes relatively common in a population because it was inherited from a shared ancestor. It may also reflect a part of the gene that is particularly vulnerable to disease-causing sequence changes. Larger studies will be needed to distinguish these possibilities and to determine how widely these variants occur beyond this Korean cohort.

Loss of function and haploinsufficiency: a key biological message

The study found that 84.2% of identified variants were predicted loss-of-function variants. These included splice-site, frameshift, and nonsense variants—changes that can substantially reduce production of a functional IMPG2 protein. Overall, 92.9% of patients carried at least one loss-of-function variant.

IMPG2 encodes a component of the interphotoreceptor matrix, the specialized environment between photoreceptors and the retinal pigment epithelium. Photoreceptors are the cells that detect light, while the retinal pigment epithelium supports their health and function. Disruption of IMPG2 can therefore disturb retinal structure and contribute to macular deposits, photoreceptor abnormalities, or more widespread retinal degeneration.

The authors conclude that IMPG2 loss of function—including haploinsufficiency—appears to be a major disease mechanism. Haploinsufficiency means that one working copy of a gene may not produce enough protein to maintain normal retinal function. This concept is especially relevant because it shapes how researchers think about potential treatments.

Implications for genetic diagnosis and future therapies

For patients with a vitelliform macular diagnosis, this research supports comprehensive genetic testing rather than assuming all Best disease-like presentations arise from BEST1. A precise molecular diagnosis may distinguish BEST1-related Best disease from IMPG2-associated retinopathy and from other inherited causes of vitelliform lesions.

The predominance of loss-of-function variants also provides a biologically clear direction for treatment research. When disease results from too little functional protein, an approach designed to restore or supplement normal gene function may be particularly relevant. The study does not test a therapy, but its findings strengthen the rationale for investigating gene-replacement or other strategies that increase functional IMPG2 activity. The recurrent splice-site variants may also make RNA-focused approaches a future research interest, since such strategies aim to correct or bypass faulty RNA processing.

Looking ahead

This small but detailed multicenter study expands the picture of IMPG2-associated retinopathy in Korea. It shows that adult-onset vitelliform macular dystrophy is a prominent presentation, identifies a strong cluster of splice-site variants, and points to loss of function as a central mechanism of disease.

Future work will need to follow larger groups over time, compare disease progression across genetic subtypes, and examine whether people with the same recurrent variant share similar retinal findings. For families affected by Best disease-like macular changes, the broader message is encouraging: increasingly precise genetic diagnosis is revealing the distinct biological pathways behind similar retinal appearances—and creating a stronger foundation for targeted treatments.