Congenital anterior segment ocular disorders: Genotype-phenotype correlations and emerging novel mechanisms

Abstract

Development of the anterior segment of the eye requires reciprocal sequential interactions between the arising tissues, facilitated by numerous genetic factors. Disruption of any of these processes results in congenital anomalies in the affected tissue(s) leading to anterior segment disorders (ASD) including aniridia, Axenfeld-Rieger anomaly, congenital corneal opacities (Peters anomaly, cornea plana, congenital primary aphakia), and primary congenital glaucoma. Current understanding of the genetic factors involved in ASD remains incomplete, with approximately 50% overall receiving a genetic diagnosis. While some genes are strongly associated with a specific clinical diagnosis, the majority of known factors are linked with highly variable phenotypic presentations, with pathogenic variants in FOXC1, CYP1B1, and PITX2 associated with the broadest spectrum of ASD conditions. This review discusses typical clinical presentations including associated systemic features of various forms of ASD; the latest functional data and genotype-phenotype correlations related to 25 ASD factors including newly identified genes; promising novel candidates; and current and emerging treatments for these complex conditions. Recent developments of interest in the genetics of ASD include identification of phenotypic expansions for several factors, discovery of multiple modes of inheritance for some genes, and novel mechanisms including a growing number of non-coding variants and alleles affecting specific domains/residues and requiring further studies.

Keywords: Aniridia; Anterior segment disorder; Axenfeld-Rieger; Corneal opacity; Heterogeneity; Peters anomaly; Primary congenital aphakia; Primary congenital glaucoma.

Fig. 1:. A timeline diagram showing ASD gene identification by year.

Genes listed by year of first identification in ASD phenotype specifically. Genes in bold associated with both dominant and recessive phenotypes.

Fig. 2:. Ocular images demonstrating anterior segment disorders.

A) Bilateral aniridia; B) Axenfeld-Rieger anomaly (ARA) with severe corectopia and peripheral corneal opacity ; C) ARA with iris hypoplasia with polycoria; D) Enlarged view of C showing residual iris tissue, lenticular opacity, and corneal surface irregularity; E) Congenital glaucoma with posterior embryotoxon and left corneal opacity; F) ARA with corectopia and polycoria; G) Slit lamp view of iridocorneal adhesions in ARA; H) ARA with posterior embryotoxon and mild corectopia; I) Peters anomaly; J) Corectopia and mild iris hypoplasia with anterior chamber intraocular lens; K) Complete corneal opacity (sclerocornea) due to congenital primary aphakia; L) Peters anomaly with corneal opacity and iridocorneal adhesions; M) severe corectopia, iris hypoplasia, and posterior embryotoxon. Causative gene is indicated in the lower left-hand corner for each image. Individuals shown in panels I-M were also presented in prior publications (Reis et al., 2023b; Reis et al., 2021; Reis et al., 2019; Reis et al., 2008).

Fig. 3:. Venn diagram showing overlapping phenotypes of genes associated with anterior segment disorders.

While some genes are associated with one specific ASD category, many are linked to variable and overlapping phenotypes. Aniridia oval includes partial aniridia and clinical phenocopies such as mydriasis; Congenital corneal opacities oval includes Peters anomaly, corneal plana, congenital primary aphakia, and other unspecified corneal opacity.