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Six NSCL/P Loci Show Associations With Normal-Range Craniofacial Variation

NCJ Number
Date Published
21 pages
This study investigated the influence of genetic variants associated with NSCL/P (non-syndromic cleft lip with/without cleft palate) on normal-range variation in facial shape.
Orofacial clefting is one of the most prevalent craniofacial malformations. Previous research has demonstrated that unaffected relatives of patients with non-syndromic cleft lip with/without cleft palate (NSCL/P) show distinctive facial features, which can be an expression of underlying NSCL/P susceptibility genes. These results support the hypothesis that genes involved in the occurrence of a cleft also play a role in normal craniofacial development. The current study conducted a literature review of genome-wide association studies (GWAS) that investigated the genetic etiology of NSCL/P, resulting in a list of 75 single nucleotide polymorphisms (SNPs) located in 38 genetic loci. Genotype data were available for 65 of these selected SNPs in three datasets with a combined sample size of 7,418 participants of European ancestry, whose 3D facial images were also available. The effect of each SNP was tested using a multivariate canonical correlation analysis (CCA) against 63 hierarchically constructed facial segments in each of the three datasets and meta-analyzed. This enabled the investigation of associations between SNPs known to be involved in NSCL/P and normal-range facial shape variations in a global-to-local perspective, without preselecting specific facial shape features or characteristics. The study found that six NSCL/P SNPs showed significant associations with variation in normal-range facial morphology, with rs6740960 showing significant effects in the chin area (p = 3.71 10-28). This SNP lies in a non-coding area. Another SNP, rs227731 near the NOG gene, showed a significant effect in the philtrum area (p = 1.96 10-16). Three SNPs showed significant effects on the shape of the nose. rs742071 (p = 8.71 10-14), rs34246903 (p = 6.87 10-12), and rs10512248 (p = 8.4 10-9). Respectively, these SNPs are annotated to PAX7, MSX1, and PTCH1. Finally, rs7590268, an intron variant of THADA, showed an effect in the shape of the supraorbital ridge (p = 3.84 10-7). Thus, this study provides additional evidence that NSCL/P-associated genetic variants influence normal-range craniofacial morphology, with significant effects observed for the chin, the nose, the supraorbital ridges and the philtrum area. (publisher abstract modified)

Date Published: January 1, 2018