Validation of Thymocyte Selection-associated High-mobility Group Box-3 Gene Mutation and Risk Identification in Non-syndromic Cleft Lip and Palate Deformities in Malay Patients - A Retrospective Study.

Abstract

Introduction: Non-syndromic cleft lip and/or palate (NSCL/P) is a common congenital deformity, influenced by both genetic and environmental factors. The thymocyte selection-associated high-mobility group box-3 (TOX3) gene is suggested to influence NSCL/P development, though its role remains unclear. This study investigates environmental factors associated with NSCL/P and explores the association between TOX3 mutations and these factors.

Materials and methods: A cross-sectional retrospective study was conducted amongst 50 Malay patients with NSCL/P who underwent surgery at Hospital Universiti Sains Malaysia (January 2022-January 2023). Participants were selected based on inclusion criteria from electronic medical records. Data on environmental and familial risk factors were obtained using validated pro formas, and TOX3 gene copy number was analysed using quantitative polymerase chain reaction.

Results: Cleft lip and palate (CL/P) were the most common deformity, accounting for 74% of cases, and 56% of patients were male. Significant risk factors for NSCL/P included consanguineous marriage, family history of clefts, maternal radiation exposure, traditional medicine use, allergies, paternal smoking and infant heart anomalies (P ≤ 0.05). Maternal pregnancy age was inversely correlated with TOX3 expression in CL/P cases (r = -0.387, P = 0.018).

Discussion: The findings highlight complex gene-environment interactions in NSCL/P aetiology. Genetic predisposition, parental exposures and maternal factors jointly increase risk. Larger studies are needed to confirm these findings and further investigate gene-environment interactions in NSCL/P. The study underscores the role of TOX3 and environmental influences in NSCL/P pathogenesis, supporting targeted prevention and genetic counselling in the Malay population.