Identifying New Susceptibility Gene of Nonsyndromic Orofacial Cleft Based on Syndromes Accompanied With Hypertelorism

ObjectivesGenetic studies of nonsyndromic orofacial clefts (NSOC) focus on identifying susceptibility genes and elucidating underlying pathogenesis. A correlation between orofacial clefts and hypertelorism has been established by previous studies, hinting at shared genetic risk factors.Materials and MethodsSyndromes characterized by hypertelorism and orofacial clefts were screened, followed by analysis and selection of their causative genes, resulting in 35 candidate genes. After genotyping quality control, 340 single nucleotide polymorphisms (SNPs) were analyzed. Allelic and genotypic associations were evaluated under the additive model with Bonferroni correction. Linkage disequilibrium and haplotype analysis were performed.ResultsSingle nucleotide polymorphisms that showed significant allelic associations with NSOC subtypes are notably within TRAPPC9, TBX1, and ZIC2 genes. Single nucleotide polymorphisms within TRAPPC9 were primarily associated with nonsyndromic cleft lip and palate (NSCLP), while SNPs within TBX1 exhibited risk and protective effects across NSCLP, nonsyndromic cleft lip only (NSCLO), and nonsyndromic cleft palate only. ZIC2 SNPs were significantly associated with NSCLP and NSCLO. Although 15 SNPs in CDH1 showed allelic association with NSCLO and were in strong linkage disequilibrium, no statistically significant genotypic or haplotypic associations were identified.ConclusionTRAPPC9, TBX1, and ZIC2 are identified as novel susceptibility genes for NSOC in the western Han Chinese population, with TRAPPC9 and TBX1 showing distinct risk and protective effects among subtypes. While further studies are required to confirm their role, these findings deepen our understanding of NSOC genetics, emphasize the importance of subtype analysis, and provide valuable directions for further mechanistic studies.