Exploring the genetic and pathobiological pathways of talipes equinovarus: a short narrative review

Abstract

Talipes equinovarus (TEV), also known as club foot, is one of the common congenital foot deformities. TEV deformity includes the components of osteochondral tissues namely supination, or inversion of the subtalar joint (hind foot varus), forefoot adduction deformity (metatarsus adductus), exaggerated midfoot arch (cavus) and limited ankle dorsiflexion (equinues). Its prevalence ranges from 0.5 to 2.0/1000 live births. It is hypothesized that TEV manifestation is due to molecular genetic defects that are influenced by environmental factors. The deformity had been recognized for centuries, but its main cause remains elusive. This narrative review summarizes the literature data that have accumulated over the past few decades on the environmental, molecular, and genetic factors along with the pathobiological mechanisms underlying TEV and analyze the role of these factors in the development of this disease. TEV segregates in families with both autosomal dominant and recessive mode of inheritance or autosomal dominant with incomplete penetrance. This supports the involvement of the genetic component underlying TEV. Genetic factor underlying TEV is further supported by the fact that a much higher concordance rate is seen in monozygotic (32%) rather than dizygotic (2.9%) twins. Various genetic studies including candidate gene association studies, copy number variation analysis, linkage analysis, whole exome sequencing and whole genome sequencing have shown the involvement of certain genes in the development of TEV. The research work done so far is still deficient for the exact genetic cause in families with TEV as most studies have focused on the sporadic cases and the genetic causes documented so far are still speculative. TEV is considered as a multifactorial congenital deformity where both genetic and environmental factors disrupt the normal mitotic division of the cytoskeleton in the lower limbs and ultimately leads to the formation of deformed foot. Hence, large multiscale, multicenter collaborative studies using genetic techniques like genome wide association studies (GWAS) with single nucleotide polymorphisms scan and linkage analysis in large families are required.