Rare Heterozygous Missense Variants in VSX2 Are Associated With Retinal Detachment

Authors

• Daniel C Brock
• Justin S Dhindsa
• Yifan Chen
• Vida Ravanmehr
• Jonathan Mitchell
• Fengyuan Hu
• Xiaoyin Li
• Likhita Nandigam
• Quanli Wang
• Kevin Wu
• Jessica C Butts
• Hardeep S Dhindsa
• Benjamin J Frankfort
• Nicholas M Tran
• Slavé Petrovski
• Ryan S Dhindsa

Language

English

Publication Date

2-1-2026

Journal

PLoS Genetics

DOI

10.1371/journal.pgen.1012027

PMID

41632798

PMCID

PMC12890223

PubMedCentral® Posted Date

2-3-2026

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Humans, Mutation, Missense, Retinal Detachment, Female, Male, Genetic Predisposition to Disease, Heterozygote, Case-Control Studies, Middle Aged, Aged, Adult, Genome-Wide Association Study, Whole Genome Sequencing, Homeodomain Proteins, Polymorphism, Single Nucleotide

Published Open-Access

yes

Recommended Citation

Brock, Daniel C; Dhindsa, Justin S; Chen, Yifan; et al., "Rare Heterozygous Missense Variants in VSX2 Are Associated With Retinal Detachment" (2026). Duncan NRI Faculty and Staff Publications. 203.
https://digitalcommons.library.tmc.edu/duncar_nri_pub/203