Anterior Segment Dysgenesis via the FOXE3 Gene

Anterior segment dysgenesis (ASD) is referred to as a developmental disorder in which the anterior segment of the eye including the iris, cornea and trabecular meshwork are affected and result in a spectrum of anomalies such as aniridia, cataracts and glaucoma that lead to visual disability in childhood (Ito and Walter 2014; Brémond-Gignac et al. 2010; Semina et al. 2001).

Genes encoding transcription factors such as PAX6, PITX2, FOXC1, FOXE3 and PITX3 have shown to be involved in the control of eye morphogenesis and therefore associated with ASD (Doucette et al. 2011). Homozygous mutations in FOXE3 (forkhead box E3) have been shown to cause non-syndromic, bilateral, total sclerocornea, aphakia, microphthalmia and optic disc coloboma (Ali et al. 2010). Also, dominant FOXE3 mutations have been reported in patients with congenital cataract and aniridia (Semina et al. 2001; Iseri et al. 2009). Dominant variants are those (e.g., c.958T>C (p.*320Argext*72) and c.942dupG (p.Leu315Alafs*117)), which result in extension of the open reading frame beyond the normal stop codon and are reported to have dominant negative effect (Semina et al. 2001; Iseri et al. 2009). Recessive variants (e.g., missense variants) result in altered protein interactions (Iseri et al. 2009). However, a recent functional analysis of six FOXE3 causative variants indicated that three recessive mutants showed loss-of-function, one retained DNA binding activity, whereas two dominant mutants showed altered activity as compared to the wild-type. However, no evidence of dominant negative action was seen in the enlarged proteins due to the c.958T>C and c.942dupG variants (Islam et al. 2015). FOXE3 encodes a forkhead transcription factor and is specifically expressed in the anterior lens epithelium (Semina et al. 2001). So far, about 10 causative variants (missense/nonsense, small deletions and insertions) have been reported in FOXE3 (Human Gene Mutation Database).

Predicting clinical sensitivity for the FOXE3 gene is challenging due to genetic heterogeneity of ASD. However FOXE3 pathogenic variants have been shown to account for 15% (4/26) of bilateral microphthalmia cases [100% of consanguineous families (3/3)], which were negative for SOX2 mutations (Reis et al. 2010).

This test involves bidirectional Sanger sequencing of all coding exons and splice sites of the FOXE3 gene. The full coding sequence of each exon plus ~10 bp of flanking DNA on either side are sequenced. We will also sequence any single exon (Test #100) or pair of exons (Test #200) in family members of patients with known pathogenic variants or to confirm research results.