Year: 2026
Type: article
Abstract: Background: Talipes equinovarus (TEV), commonly known as clubfoot, is a congenital skeletal deformity characterized by abnormal three-dimensional positioning of the foot, ankle, and lower limb. This condition arises from developmental anomalies affecting multiple tissues in the lower limb, leading to disrupted alignment of foot and ankle joints. Without timely and appropriate intervention, TEV can result in persistent pain, structural deformities, and long-term functional impairments. Summary: TEV is a congenital skeletal (musculoskeletal) disorder with unresolved molecular etiology. However, human genetic studies have identified rare variants and structural alterations in critical lower-limb patterning regulators such as the PITX1-TBX4 transcriptional axis and posterior HOX genes; however, these findings explain only a fraction of cases. The limited explanatory power of currently known genes points to substantial genetic heterogeneity and involvement of regulatory noncoding variants, polygenic risk, and genetic-environment interactions. In this review, we critically integrate existing human genetic and developmental evidence and identify key gaps in genotype-phenotype correlation that must be addressed to understand the underlying pathophysiological of TEV. The etiology of TEV involves a multifactorial interplay between genetic susceptibility and environmental influences. Familial aggregation and phenotypic variability within and between affected individuals support a heritable component in TEV pathogenesis. Genetic studies have implicated variants in genes encoding skeletal muscle contractile proteins and key developmental regulators, including TBX4, PITX1, and HOX clusters (HOXA, HOXC, HOXD), as well as NAT2. However, no singular high-penetrance gene has been definitively linked to TEV. The molecular pathways by which these genetic variants confer risk, and their genomic and proteomic interactions, require further elucidation. Key Message: Enhancing our understanding of the genetic architecture and signaling pathways involved in TEV is essential to reveal the complex pathophysiology of this condition and may inform improved diagnostic and therapeutic strategies.
Source: Molecular Syndromology
DOI: 10.1159/000550832
Author: Saad Almohrij
Language: English
Subfield: Developmental Biology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W7127438174