FOXC1 – Axenfeld Anomaly

Axenfeld anomaly is an autosomal dominant anterior segment dysgenesis characterized by posterior embryotoxon, iris strands, and elevated risk of glaucoma and vision loss. FOXC1 (HGNC:3800) variants have been repeatedly implicated in this condition. Two pedigrees demonstrated heterozygous FOXC1 mutations segregating fully with disease: a novel wing region missense variant in an Indian family (3 probands)[PMID:12454026] and c.272T>C (p.Ile91Thr) in a four-generation kindred (10 affected)[PMID:15477465].

Genetic evidence supports haploinsufficiency as the mechanism. A total of 13 probands (3[PMID:12454026]; 10[PMID:15477465]) with autosomal dominant inheritance and family segregation meet criteria for a definitive gene–disease relationship, with variant spectrum including missense substitutions within the forkhead domain, frameshift mutations, and gene dosage alterations[PMID:9620769]. One representative pathogenic variant is c.272T>C (p.Ile91Thr).

Functional assays in cultured cells (DNA-binding and transactivation) demonstrated that disease-associated FOXC1 mutations reduce forkhead domain activity[PMID:11179011]. Additionally, zebrafish foxc1a/b knockout models recapitulate anterior segment defects and glaucoma phenotypes, reinforcing haploinsufficiency as the pathogenic mechanism[PMID:32720677].

Although some rare FOXC1 variants have been identified in broad developmental eye anomaly cohorts without clear pathogenicity, bona fide pathogenic alleles cluster in the conserved forkhead region and consistently show deleterious functional effects. No studies have refuted the FOXC1–Axenfeld anomaly association.

In summary, FOXC1 haploinsufficiency is a definitive cause of autosomal dominant Axenfeld anomaly. Clinical genetic testing for FOXC1 variants is indicated in patients with anterior segment dysgenesis, enabling accurate diagnosis, prognosis, and management.

Key Take-home: FOXC1 sequencing should be included in diagnostic workflows for Axenfeld anomaly to guide clinical management.

References

• Investigative Ophthalmology & Visual Science | 2002 | Novel mutation in FOXC1 wing region causing Axenfeld-Rieger anomaly PMID:12454026
• Archives of Ophthalmology | 2004 | Axenfeld-Rieger anomaly: a novel mutation in the forkhead box C1 (FOXC1) gene in a 4-generation family PMID:15477465
• Nature Genetics | 1998 | The forkhead transcription factor gene FKHL7 is responsible for glaucoma phenotypes which map to 6p25 PMID:9620769
• 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 | 2020 | Disruption of foxc1 genes in zebrafish results in dosage-dependent phenotypes overlapping Axenfeld-Rieger syndrome PMID:32720677

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