Truncating PAX6 mutations result in severe arrested retinal development with loss of cone photoreceptor specialisation: A multi-centre study

Abstract

Purpose : PAX6 variants can be associated with pan-ocular phenotypes such as aniridia, keratopathy, anterior segment dysgenesis, cataracts, colobomas, foveal hypoplasia and optic nerve hypoplasia. Previous genotype-phenotype correlation studies have shown strong correlation between the severity of aniridia associated phenotypes and the type of PAX6 variants. In this multi-centre study, we aimed to specifically characterise the foveal phenotypes associated with PAX6 variants.

Methods : We established the foveal development investigators group (FDIG) aimed at exploring foveal phenotypes in developmental retinal disorders across different centres (n=10) in 8 countries. We included all patients with pathogenic PAX6 variants and high-resolution optical coherence tomography (OCT) scans of the fovea from FDIG and the literature. Variants were classified into truncating and non-truncating based on predicted effect. Foveal OCTs were graded by at least two expert graders and classified into grades of foveal hypoplasia according to the classification by Thomas MG et al. 2011. The groups were further classified into with cone photoreceptor specialisation (PRS+) and without (PRS-).

Results : We identified a total of 106 patients that met the inclusion criteria. There were more cases with truncating mutations (n=71) compared to non-truncating mutations (n=35). Grade 4 foveal hypoplasia was the most common (40.6% of cases). There was a significantly higher proportion of PRS- cases associated with truncating variants (X2 = 12.6, p=0.0004) compared to non-truncating variants. The visual acuity was significantly worse for truncating variants compared to non-truncating variants (median difference=0.35 logMAR, p<0.0001).

Conclusions : We show that truncating PAX6 variants are associated with severe arrested retinal development with loss of cone photoreceptor specialisation. These loss-of-function variants are predicted to generate no protein and hence result in relatively severe foveal phenotypes compared to missense variants. This also translates to poorer visual acuity in patients with truncating PAX6 variants.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.