Genetic Analysis of Preaxial Polydactyly: Identification of Novel Mutations and the Role of ZRS Duplications in a Chinese Cohort of 102 cases

Abstract

Background: Preaxial polydactyly (PPD) is a congenital limb malformation, previously reported to be caused primarily by mutations in the ZRS and upstream preZRS regions. This study investigated genetic variations associated with PPD, focusing on point mutations and copy number variations (CNVs) in the ZRS and preZRS regions. Methods: Comprehensive genetic analyses were conducted on 102 patients with PPD, including detailed clinical examinations and Sanger sequencing of the ZRS and preZRS regions. Additionally, real-time quantitative PCR (qPCR) was used to detect CNVs in the ZRS region. The evolutionary conservation and population frequencies of identified mutations were also evaluated. Results: Six point mutations were identified, including four novel mutations with potential pathogenicity, namely, 93G > T (chr7:156584477), 106G > A (chr7:156584464), 278G > A (chr7:156584292), and 409A > C (chr7:156585378). Additionally, qPCR analysis revealed that 66.67% of patients exhibited ZRS duplications. Notably, these duplications were also present in cases with newly identified potential pathogenic point mutations. These findings suggest the possible interaction of point mutations in ZRS and preZRS through a common pathogenic mechanism, leading jointly to PPD. Conclusion: The findings expand the mutation spectrum associated with non-syndromic polydactyly and highlight that, despite different classifications, anterior polydactyly caused by mutations in ZRS and nearby regions may share common pathogenic mechanisms. The incorporation of various mutation types in genetic screening can effectively enhance the rate of pathogenic mutation detection and contribute to the cost-effectiveness of genetic testing for limb developmental defects, thereby promoting healthy births.