FOXE3 – Peters Anomaly

FOXE3 is a lens-specific forkhead transcription factor essential for anterior segment development. Heterozygous extension variants in FOXE3 cause autosomal dominant ocular anterior segment dysgenesis, notably Peters anomaly, characterized by central corneal opacity and irido-lenticulo-corneal adhesions. Experimental and clinical data converge to support a dosage-sensitive mechanism whereby C-terminal alterations lead to variable phenotypic expressivity, including Peters anomaly. The association between FOXE3 and Peters Anomaly has been demonstrated in multiple independent pedigrees with segregation and functional studies.

In a Newfoundland family, a novel non-stop variant c.959G>T (p.Ter320Leu) segregated with anterior segment anomalies in 11 affected relatives under an autosomal dominant model (PMID:21150893). Two additional heterozygous C-terminal extension mutations were reported in separate pedigrees, each with Peters anomaly among other anterior segment defects (PMID:19708017). No FOXE3 mutations were detected in a Saudi Arabian cohort of Peters anomaly patients, suggesting population-specific alleles or locus heterogeneity (PMID:15621878).

The variant spectrum includes non-stop extension alleles such as c.959G>T (p.Ter320Leu) and recessive missense/truncating variants with distinct phenotypes. Dominant alleles predict addition of 72 residues at the C-terminus, whereas recessive forkhead domain missense and truncating variants result in severe microphthalmia and corneal opacity without Peters anomaly. The recurrent use of C-terminal extension variants across pedigrees underlies a founder-independent mechanism for dominant Peters anomaly.

Functional assays of dominant FOXE3 variants demonstrate loss of normal stop codon leading to reduced protein stability, altered nuclear localization, and impaired transcriptional activation (PMID:25504734). Band-shift and reporter assays confirm that extension proteins have dominant-negative characteristics rather than simple haploinsufficiency. In vitro data align with the variable expressivity observed in patients, reinforcing a mechanism of altered protein function.

Evidence against a major role for FOXE3 in all populations comes from the absence of coding mutations in a Saudi cohort of 11 families with Peters anomaly (PMID:15621878). This highlights genetic heterogeneity and the need to consider population-specific mutation spectra and potential modifiers when interpreting negative results.

Collectively, genetic segregation in multiple families and robust functional data support a Moderate ClinGen classification for FOXE3–Peters anomaly. Clinical testing of FOXE3 should include screening for non-stop extension variants to inform diagnosis and family counseling. Key Take-home: Autosomal dominant FOXE3 extension mutations are a clinically actionable cause of Peters anomaly, warranting inclusion in diagnostic panels.

References

• Ophthalmic genetics | 2004 | Molecular basis of Peters anomaly in Saudi Arabia. PMID:15621878
• Human mutation | 2009 | Seeing clearly: the dominant and recessive nature of FOXE3 in eye developmental anomalies. PMID:19708017
• European Journal of Human Genetics | 2011 | A novel, non-stop mutation in FOXE3 causes an autosomal dominant form of variable anterior segment dysgenesis including Peters anomaly. PMID:21150893
• Human mutation | 2015 | Functional analysis of FOXE3 mutations causing dominant and recessive ocular anterior segment disease. PMID:25504734

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