# Rare heterozygous missense variants in VSX2 are associated with retinal detachment

## TL;DR

Rare genetic changes in the VSX2 gene are linked to an increased risk of retinal detachment in adults.

## Contribution

Identified rare heterozygous missense variants in VSX2 as a novel genetic risk factor for retinal detachment.

## Key findings

- Rare heterozygous missense variants in VSX2 increase RD risk by 2.8-fold.
- The p.Glu218Asp variant in VSX2 shows a strong effect size with an odds ratio of 5.9.
- VSX2 variants demonstrate a gene dosage effect, with homozygous mutations causing severe eye disorders and heterozygous variants causing adult-onset RD.

## Abstract

Retinal detachment (RD) is a sight-threatening emergency requiring urgent intervention to prevent permanent vision loss. While both environmental and genetic risk factors contribute to RD, its complete genetic architecture remains unknown. Here, we performed the largest whole genome sequencing-based case-control study in RD to date, including data from 7,276 RD cases and 236,741 controls in the UK Biobank. Through variant- and gene-level association analyses, we identified VSX2 as a genetic determinant of RD risk while confirming established associations including FAT3, RDH5, and COL2A1. Gene-level collapsing analysis revealed that rare heterozygous missense variants in VSX2 confer a 2.8-fold increased risk of RD (p = 2.4x10-10; odds ratio (OR) = 2.8; 95% confidence interval (CI): [2.1, 3.7]). One missense variant in this gene, p.Glu218Asp, demonstrated a particularly strong effect size (p = 9.3x10-10; OR = 5.9; 95% CI: [3.7, 9.4]). Replication analyses in two additional cohorts, totaling 1,331 cases and 52,355 controls strengthened both the gene- and variant-level associations even further (p = 1.4x10-10 and 1.1x10-11, respectively). Other contributory heterozygous variants included previously reported pathogenic homozygous variants for anophthalmia and microphthalmia. These findings thus reveal a previously unknown gene dosage curve for VSX2, where homozygous mutations cause severe developmental eye disorders and heterozygous mutations cause adult-onset retinal detachment. Extending this observation, we found a significant enrichment for other known recessive Mendelian eye disease genes among nominally significant (p < 0.05) genes associated with RD in the collapsing analysis. This work provides a compelling example of how heterozygous variants in recessive disease genes can be associated with less severe clinical phenotypes.

Retinal detachment (RD) is a medical emergency that can lead to permanent blindness if not treated promptly. Although both environmental and genetic factors contribute to RD risk, much of its genetic basis has remained unclear. In this study, we analyzed whole genome sequencing data from more than 240,000 individuals in the UKBiobank, representing the largest genetic study of RD to date. We discovered that rare variants in VSX2, a gene essential for retinal development, substantially increase RD risk in adults, independent of known risk factors such as myopia or cataract. We further confirmed this association in two independent cohorts: All of Us and 100kGP. While homozygous VSX2 variants are known to cause severe childhood eye conditions like microphthalmia or anophthalmia, our findings demonstrate that carrying a single altered copy of VSX2 increases susceptibility to RD later in life, expanding the phenotypic spectrum of this gene. We also found that heterozygous variants in other genes linked to recessive eye diseases may similarly increase RD risk. Collectively, these findings reveal connections between rare developmental disorders and common adult disease, illustrating how large-scale genomic analysis can uncover hidden contributors to vision loss and inform future strategies for early detection.