HOXD10 – Congenital Vertical Talus

HOXD10 encodes a homeodomain transcription factor critical for limb patterning and skeletal development. Congenital vertical talus (CVT; “rocker-bottom foot”) is a rigid dorsal dislocation of the talonavicular joint leading to a convex plantar surface. Familial CVT has been linked to mutations in genes within the HOXD cluster, most notably HOXD10. The strength of evidence for HOXD10 in isolated CVT has steadily increased through pedigree analyses and functional studies.

In an initial report, four generations of a single pedigree exhibited radiographically confirmed CVT; HOXD10 mutation status was assessed in 14 affected individuals (including two with Charcot-Marie-Tooth-like foot deformity) and 20 unaffected relatives, revealing complete segregation of a HOXD10 variant in all affected but none of the unaffected family members (n=14) (PMID:15368082). Penetrance was complete in this autosomal dominant pedigree. Clinical and radiologic evaluation across infancy to adulthood demonstrated variable severity but consistent presence of CVT, supporting a primary role for HOXD10 in foot morphogenesis.

A second independent study of a 36-member multigenerational family defined a 7 Mb linkage region on chromosome 2q31, leading to sequencing of HOXD10. A single missense variant, c.956T>A (p.Met319Lys), fully co-segregated with both CVT and Charcot-Marie-Tooth phenotypes and exhibited significant linkage with a LOD score of 6.33 (θ=0) (PMID:15146389). This mutation was observed in all clinically affected heterozygotes, confirming autosomal dominant inheritance with complete penetrance.

Genetic evidence is robust: two unrelated pedigrees, >14 affected relatives, full co-segregation, and high-confidence linkage to HOXD10 variants. Only missense changes have been reported in CVT, with c.956T>A (p.Met319Lys) as the sole recurrent variant. No loss-of-function or splice variants have been described in this context, and no population-specific founder effects have been reported.

Functional studies support a developmental role for HOXD10 but have not directly modeled CVT. In human embryonic kidney HEK293 cells, HOXD10 interacts with TBX1 to modulate TGF-β/BMP signaling (PMID:22842189). In mice, combined loss of Hoxa9,10,11 and Hoxd9,10,11 results in zeugopod and stylopod defects with altered Shh and Fgf8 expression, implicating Hoxd10 in limb skeletal patterning (PMID:26186931). These data are concordant with a haploinsufficiency mechanism.

No studies have disputed the association between HOXD10 variants and CVT, and no alternative genes have shown comparable segregation or linkage. The phenotypic spectrum remains narrowly defined to foot dorsiflexion anomalies with rigid dislocation.

In summary, HOXD10 variants cause autosomal dominant CVT with complete penetrance and strong genetic linkage, supported by developmental functional data. Clinical sequencing of HOXD10 is recommended for individuals with familial CVT to confirm diagnosis, guide management, and enable genetic counseling. Key take-home: HOXD10 missense mutations are a definitive molecular basis for congenital vertical talus.

References

• Skeletal Radiology • 2004 • Congenital vertical talus in four generations of the same family. PMID:15368082
• American Journal of Human Genetics • 2004 • A HOX gene mutation in a family with isolated congenital vertical talus and Charcot-Marie-Tooth disease. PMID:15146389
• Gene • 2014 • Interaction between Tbx1 and Hoxd10 and connection with TGFβ-BMP signal pathway during kidney development PMID:22842189
• BMC Developmental Biology • 2015 • Key pathways regulated by HoxA9,10,11/HoxD9,10,11 during limb development. PMID:26186931

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