Identifying New Susceptibility Genes of Non-Syndromic Orofacial Cleft Based on Syndromes Accompanied With Craniosynostosis.

Objectives: Orofacial cleft (OC) can be classified into syndromic orofacial cleft (SOC) and non-syndromic orofacial cleft (NSOC), depending on whether there are other congenital deformities. Craniosynostosis, the premature closure of cranial sutures, is a common phenotype of SOC resulting in abnormal ossification of skull and brain development disorders. Its correlation with OC offers a promising approach to identify susceptibility genes for NSOC by examining causative genes of SOCs with craniosynostosis.

Materials And Methods: This study included 2556 patients with NSOC and 2255 normal controls from western Han Chinese with their genomic DNA samples. We selected 31 causative genes of 34 syndromes with both craniosynostosis and OC as candidate genes and performed quality control. Allelic and genotypic association analyses and haplotype analysis were performed to identify statistically significant single nucleotide polymorphisms (SNPs).

Results: In allelic association analysis performed with 1265 qualified SNPs in 20 genes, only rs2239936, located in gene, was statistically associated with non-syndromic cleft lip only (NSCLO) (= 1.70×10, OR=1.33, 95%CI: 1.17-1.52) and non-syndromic cleft palate only (NSCPO) (= 6.43×10, OR=1.33, 95%CI: 1.16-1.52). The higher frequency of allele G in NSCPO suggesting that minor allele G at rs2239936 will result in an elevated risk of NSCPO. However, rs2239936 only exhibited a statistical association with NSCPO in genotypic association analysis (= 8.06×10) and haplotype analysis (= 1.43×10).

Conclusion: This study identified that allele G at rs2239936 in gene was significantly associated with NSCPO as a risk factor and was a new susceptibility gene for NSCPO in western Han Chinese population.