Association of CDKAL1nucleotide variants with the risk of non-syndromic cleft lip with or without cleft palate

Although the aetiology of non-syndromic cleft lip with or without cleft palate (nsCL/P) has been studied extensively, knowledge regarding the role of genetic factors in the pathogenesis of this common craniofacial anomaly is still limited. We conducted a follow-up association study to confirm that CDKAL1nucleotide variants identified in our genome-wide association study (GWAS) for nsCL/P are associated with the risk of this anomaly. In addition, we performed a sequence analysis of the selected CDKAL1exons. A mega-analysis of the pooled individual data from the GWAS and a replication study revealed that six out of thirteen CDKAL1variants were positively replicated and reached the threshold of statistical significance (Ptrend< 3.85E−03). They represented a single association signal and were located within the fifth intron of CDKAL1. The strongest individual variant was rs9356746 with a Ptrendvalue = 5.71E−06 (odds ratio (OR) = 1.60, 95% confidence interval (CI): 1.30–1.97). Sequencing analysis did not reveal any pathogenic mutations of this gene. This study provides the first evidence that chromosomal region 6p22.3 is a novel susceptibility locus for nsCL/P. The location of the risk variants within the CDKAL1intronic sequence containing enhancer elements predicted to regulate the SOX4transcription may suggest that SOX4, rather than CDKAL1, is a potential candidate gene for this craniofacial anomaly.