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Congenital vertical talus (CVT), or rocker-bottom foot, is a rare pediatric foot deformity marked by rigid dorsiflexion and hindfoot equinus due to talonavicular joint dislocation. CVT can present as an isolated anomaly or within multisystem syndromes, and is clinically heterogeneous with both simplex and familial occurrence. Genetic etiologies include SNVs and CNVs in developmental genes affecting limb patterning.
A recent whole-exome sequencing study of 62 CVT probands identified likely causative variants in known genes in 19/62 cases (30.6 %) (PMID:35487415). Among these, TSHZ1 harbored likely pathogenic SNVs in at least three unrelated probands and a chromosomal deletion encompassing TSHZ1 in one additional case (PMID:35487415). Familial CVT (12/62) showed a 75 % diagnostic yield compared to 20 % in sporadic cases, underscoring segregation within families (PMID:35487415).
TSHZ1 variants identified include a frameshift insertion c.187_188insACCC (p.Pro63HisfsTer8), consistent with haploinsufficiency. The recurrent identification of heterozygous loss-of-function alleles in unrelated CVT probands supports an autosomal dominant inheritance mode with at least one documented affected relative showing segregation (PMID:35487415).
Variant spectrum in CVT demonstrates a predominance of SNVs over CNVs overall; for TSHZ1 specifically, frameshift and deletion events have been observed. The frameshift insertion c.187_188insACCC (p.Pro63HisfsTer8) is predicted to introduce a premature termination codon leading to haploinsufficiency.
To date, no functional or animal model studies have directly assessed the impact of TSHZ1 truncating variants on talus development in CVT. The developmental role of TSHZ1 in limb morphogenesis suggests pathogenic haploinsufficiency, but experimental validation in cellular or model systems remains lacking.
Overall, heterozygous loss-of-function variants in TSHZ1 have been reported in multiple unrelated CVT probands with segregation in at least one family, supporting a Moderate level of gene-disease association. Screening of TSHZ1 should be considered in familial and sporadic CVT cases to improve molecular diagnosis and genetic counseling.
Gene–Disease AssociationModerateThree unrelated probands with likely causative TSHZ1 variants and one familial segregation (PMID:35487415) Genetic EvidenceModerateIdentified likely pathogenic TSHZ1 frameshift and deletion events in three unrelated CVT probands with segregation in a family (PMID:35487415) Functional EvidenceLimitedNo functional or experimental studies on TSHZ1 variants in CVT have been reported |