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FOXC1 – Peters anomaly

Peters anomaly (MONDO:0011414) is a rare congenital anterior segment dysgenesis characterized by corneal opacity, iridocorneal adhesions, and variable ocular features. A recent study identified a heterozygous de novo FOXC1 variant, c.310A>G (p.Ile104Val), in an unrelated patient with isolated PA type 1, confirmed by Sanger sequencing and absent in both parents and population controls (PMID:40650233). This single proband provides preliminary clinical evidence for FOXC1 involvement in Peters anomaly but lacks additional familial segregation or recurrence data.

Experimental characterization of FOXC1 missense variants within the forkhead domain demonstrates that substitutions at key residues impair DNA binding and transactivation, disrupt nuclear localization, and reduce protein stability, consistent with a haploinsufficiency mechanism underlying anterior segment malformations (PMID:11179011; PMID:14506133). Although these assays were not performed on p.Ile104Val specifically, they underscore the functional sensitivity of FOXC1 to missense mutations. No additional pathogenic FOXC1 variants have been reported in Peters anomaly cohorts to date, and negative screening studies suggest a limited role for FOXC1 relative to other genes in PA.

Key Take-home: Current evidence for FOXC1 in Peters anomaly is limited to a single de novo variant; FOXC1 screening may be considered after exclusion of more frequently implicated genes, but further cases and segregation studies are required to establish its diagnostic utility.

References

  • International journal of molecular sciences • 2025 • Novel Genetic Variants and Clinical Profiles in Peters Anomaly Spectrum Disorders PMID:40650233
  • American journal of human genetics • 2001 • Analyses of the effects that disease-causing missense mutations have on the structure and function of the winged-helix protein FOXC1 PMID:11179011
  • Human molecular genetics • 2003 • Structural and functional analyses of disease-causing missense mutations in the forkhead domain of FOXC1 PMID:14506133

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

One de novo FOXC1 variant (c.310A>G (p.Ile104Val)) in an unrelated Peters anomaly patient without further segregation or recurrence supports a preliminary association

Genetic Evidence

Limited

Single de novo likely pathogenic FOXC1 variant identified in one PA proband (PMID:40650233)

Functional Evidence

Moderate

Multiple in vitro studies demonstrate that FOXC1 missense mutations impair DNA binding and transactivation, consistent with haploinsufficiency (PMID:11179011; PMID:14506133)