U.S. flag

An official website of the United States government, Department of Justice.

The Intersection of the Genetic Architectures of Orofacial Clefts and Normal Facial Variation

NCJ Number
Frontiers in Genetics Dated: 2021
Date Published

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)

Date Published: January 1, 2021