HOXA13 – Hand-Foot-Genital Syndrome

Hand-Foot-Genital Syndrome (HFGS) is an autosomal dominant malformation syndrome characterized by distal limb anomalies (e.g., shortened metacarpals/metatarsals, clinodactyly) and urogenital defects (e.g., hypospadias, uterus didelphys) (HP:0040064, HP:0000047, HP:0000126, HP:0003762). Onset is congenital, and penetrance is high, with variable expressivity across families. HFGS is caused by heterozygous mutations in the HOXA13 transcription factor, which plays a critical role in distal limb and genitourinary tract development.

Genetic evidence spans over 10 unrelated families and at least 11 affected probands with diverse variant classes: nonsense (e.g., c.407C>A (p.Ser136Ter)), missense (c.1123G>T (p.Val375Phe)), frameshift (c.741dup (p.Gly248fs)), polyalanine expansions (c.366_389dup (p.Ala133_Ser134insAlaAlaAlaAlaAlaAlaAlaAla)), and multi‐gene deletions encompassing HOXA13 [PMID:10839976; PMID:19591980; PMID:27649277; PMID:28947713; PMID:36702441]. Segregation analysis in a four‐generation pedigree revealed 5 additional affected relatives carrying a HOXA13 duplication (c.360_377dup (p.Ala128_Ala133dup)) [PMID:36702441].

Functional studies confirm pathogenicity via loss of DNA binding and transcriptional activity: the recurrent homeodomain missense variant c.1123G>T (p.Val375Phe) impairs EPHA7 promoter activation in luciferase assays [PMID:28947713], and chromatin immunoprecipitation in limb tissue demonstrates HOXA13 repression of the BMP antagonist Sostdc1 in vivo [PMID:17200107]. Animal models of polyalanine expansions further support a dominant‐negative effect on posterior Hox gene function [PMID:11543619].

No published reports have refuted the HOXA13–HFGS association. Rare control cohorts and non‐HFGS uterovaginal septa cases lack HOXA13 mutations, underscoring specificity [PMID:19591980].

In sum, >10 families with >11 probands, consistent autosomal dominant segregation, and concordant functional data establish a definitive gene–disease relationship. Routine genetic testing for HOXA13 coding and GC‐rich regions is clinically indicated in patients with congenital limb and genitourinary anomalies.

Key Take-home: Heterozygous HOXA13 variants cause HFGS with high penetrance; genetic confirmation guides surveillance for associated urogenital malformations and informs reproductive counseling.

References

• American Journal of Human Genetics • 2000 • Novel HOXA13 mutations and the phenotypic spectrum of hand-foot-genital syndrome PMID:10839976
• Fertility and Sterility • 2010 • A novel mutation of HOXA13 in a family with hand-foot-genital syndrome and the role of polyalanine expansions in the spectrum of Müllerian fusion anomalies PMID:19591980
• American Journal of Medical Genetics Part A • 2017 • Familial deletion of the HOXA gene cluster associated with Hand-Foot-Genital syndrome and phenotypic variability PMID:27649277
• Journal of Genetics • 2017 • A missense mutation of HOXA13 underlies hand-foot-genital syndrome in a Chinese family PMID:28947713
• European Journal of Medical Genetics • 2023 • Hand-foot-genital syndrome due to a duplication variant in the GC-rich region of HOXA13 PMID:36702441
• The Journal of Biological Chemistry • 2007 • Elucidation, quantitative refinement, and in vivo utilization of the HOXA13 DNA binding site PMID:17200107

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