Correlation of RUNX2 Variants With Craniofacial-Dental Phenotypes in Cleidocranial Dysplasia

Cleidocranial dysplasia (CCD) is a rare RUNX2-related skeletal disorder characterized by craniofacial anomalies and skeletal Class III malocclusion. However, the relationship between RUNX2 variant type and phenotype severity remains unclear. This study aimed to evaluate the association between RUNX2 variant types and the severity of skeletal Class III malocclusion and dental anomalies in CCD.

This cross-sectional study included 11 unrelated Thai CCD probands and 14 relatives who underwent exome or genome sequencing. RUNX2 variants were classified as non-truncating or truncating/structural according to ACMG-AMP criteria. Nine genetically confirmed individuals met the inclusion criteria for radiographic analysis. Craniofacial parameters and dental anomalies were assessed using lateral cephalograms and cone-beam computed tomography. Group comparisons were performed using nonparametric tests and correlation analysis.

Truncating/structural variants were associated with shorter cranial base length, smaller SNA, and reduced nasolabial angles compared with non-truncating variants. The variant type correlated with these parameters. Skeletal Class III malocclusion was present in both groups, predominantly due to mandibular prognathism. No significant association was found between variant type and the burden or distribution of dental anomalies.

RUNX2 variant type influences cranial base and maxillary morphology, contributing to skeletal Class III severity in CCD, whereas dental anomalies appear independent of variant type.