IDENTIFICATION OF GENOMIC VARIANTS IN CONGENITAL TALIPES EQUINOVARUS FAMILIES THROUGH WHOLE EXOME SEQUENCING

Abstract

Congenital talipes equinovarus (CTEV), or clubfoot, is hindfoot varus, metatarsus adducts, cavus, and equines, with a birth prevalence of 1�4 per 1000 live births. Approximately 80% of cases are isolated, while 20% are syndromic. This study aimed to identify disease-causing genomic variants in CTEV-affected families using whole exome sequencing (WES) and Sanger validation. For this purpose, six families were analysed from Saudi Arabia and Pakistan, comprising both isolated and syndromic CTEV cases. DNA from affected and unaffected members underwent WES, followed by Sanger sequencing for segregation analysis. Family A had a ZNF384 variant that did not segregate. Family B showed CTEV with peroneal nerve involvement evident on nerve conduction studies, but no causal variant. Family C had a segregating ADGRA2 (c.298C>T; p.Arg100Cys) variant. Family D had OBSL1, MAN2B1, and SH3PXD2B variants, with SH3PXD2B (c.280C>G; p.Arg94Gly) linked to FTHS. Family E had PIEZO2 (c.273_279delACCTGGC; p.Pro92fs*18) and SH2B3, with PIEZO2 segregating. Family F had ASB15 and KIR2DL4 variants, but no segregation. Protein modeling was done for PIEZO2, ADGRA2, and MAN2B1. We identified novel ADGRA2 and PIEZO2 genes with an autosomal recessive pattern of inheritance, alongside expanded phenotypes of peroneal nerve involvement. Variants in other genes suggest indirect roles, emphasizing the need for further genomic studies and genetic testing for personalised management.