FOXD3 – Anterior Segment Dysgenesis

FOXD3 has been implicated in human anterior segment dysgenesis through the identification of rare, evolutionarily conserved variants in a cohort of 310 probands with developmental ocular anomalies. Six nonsynonymous FOXD3 variants were discovered, four of which (c.47C>T (p.Thr16Met), c.359C>T (p.Pro120Leu), c.517A>C (p.Asn173His), c.818_829dup (p.Arg273_Gly276dup)) were significantly enriched in patients with aniridia or Peters anomaly (PMID:22815627). The c.517A>C (p.Asn173His) change was observed in two unrelated affected individuals and affects a residue in the highly conserved forkhead domain, while c.818_829dup (p.Arg273_Gly276dup) was detected in three unrelated cases and absent in controls.

Functional analyses in zebrafish demonstrate that loss of foxd3 ablates neural crest progenitor maintenance and depletes neural crest–derived anterior segment structures, with rescue achieved by PAC clone injections containing foxd3 (PMID:17013879). Together, these data support a model of autosomal dominant, incompletely penetrant FOXD3 variants that increase risk for anterior segment dysgenesis. Additional studies with larger pedigrees and targeted functional assays at the ocular anterior segment are needed to confirm pathogenicity and inform diagnostic testing.

Key Take-home: FOXD3 heterozygous variants confer a modest, incompletely penetrant risk for anterior segment dysgenesis, warranting inclusion in gene panels for congenital anterior segment anomalies.

References

• Molecular Vision | 2012 | Analysis of FOXD3 sequence variation in human ocular disease. PMID:22815627
• Developmental Dynamics | 2006 | The mother superior mutation ablates foxd3 activity in neural crest progenitor cells and depletes neural crest derivatives in zebrafish. PMID:17013879

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