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ABSTRACT
Background: Orofacial clefts (OFCs) are common congenital anomalies resulting from complex genetic and environmental interactions. Multiplex families are hypothesised to carry a higher burden of genetic risk factors. Beyond the overt clefts, recent evidence suggests that unaffected relatives in these families may exhibit subtle differences in facial morphology, representing subclinical manifestations. This study aimed to investigate and characterise these facial variations among individuals from multiplex families with OFCs compared to unrelated, unaffected controls.
Method: The study involved 10 multiplex families and 275 unrelated controls. Using the VectraTM 3D camera, 3D facial images and clinical data were collected from participants. Twenty-seven facial landmarks were annotated to measure 22 features relevant to orofacial morphology. Statistical analyses were performed in R using Shapiro-Wilk tests, Wilcoxon Rank Sum tests, and multiple regression models, adjusting for confounders like sex, age, ethnicity, and BMI. To adjust for multiple testing, the Bonferroni correction was employed (p.adj < 0.00227).
Results: Facial morphometrics analysis revealed distinctive traits in both individuals affected with OFCs and unaffected relatives. Affected families exhibited significantly longer alar width (39.42 ± 3.23 vs. 37.53 ± 1.53; p.adj < 0.000713) and a reduced nasofrontal angle (141.07 ± 1.02° vs. 141.71 ± 1.55°; p.adj < 0.000776) compared to controls. Furthermore, unaffected relatives showed significantly longer philtrum length (13.98 ± 1.36 vs. 12.81 ± 0.84; p.adj < 8.11E-05), labial fissure length (51.88 ± 4.74 vs. 48.46 ± 1.41; p.adj < 0.001248), alar length (23.88 ± 2.13 vs. 22.3 ± 0.87; p.adj < 0.000287), and nasal bridge length (52.87 ± 3.18 vs. 50.67 ± 1.54; p.adj < 0.001523).
Conclusion: Our findings suggest that individuals affected with OFCs and unaffected relatives exhibit distinct facial features, including alar width, nasofrontal angle, philtrum length, and nasal bridge length. These traits serve as powerful indicators for identifying genetic risk beyond the overt clefts.