This study tested the hypothesis that unaffected relatives of individuals with non-syndromic cleft lip with or without cleft palate (NSCL/P) show distinctive facial features and that the presence of this facial endophenotype is potentially an expression of underlying genetic susceptibility to NSCL/P in the larger unselected population.
To test this hypothesis, the study first partitioned the face into 63 partially overlapping regions representing global-to-local facial morphology and then defined endophenotypic traits by contrasting the 3D facial images from 264 unaffected parents of individuals with NSCL/P compared with 3,171 controls. This analysis observed distinct facial features between parents and controls across 59 global-to-local facial segments at nominal significance (p ≤ 0.05) and 52 segments at Bonferroni corrected significance (p < 1.2 × 10–3), respectively. Next, the analysis quantified these distinct facial features as univariate traits in another dataset of 8,246 unaffected European individuals and performed a genome-wide association study. This effort identified 29 independent genetic loci that were associated (p < 5 × 10–8) with at least one of the tested endophenotypic traits, and nine genetic loci also passed the study-wide threshold (p < 8.47 × 10–10). Of the 29 loci; 22 were in proximity of loci previously associated with normal facial variation; 18 were near genes that show strong evidence in orofacial clefting (OFC); and another 10 showed some evidence in OFC. In addition, polygenic risk scores for NSCL/P showed associations with the endophenotypic traits. This study thus supports the hypothesis of a shared genetic architecture of normal facial development and OFC. (publisher abstract modified)