Mandibular morphogenesis: Genetic insights into malocclusion from EVC perspective

To investigate the association between an EVC gene single nucleotide polymorphism (rs1383180; G > A; R > Q) and mandibular skeletal malocclusion in the Mazandaran people of Northern Iran.

At the Arash Orthodontic Clinic in Babol, Iran, 393 individuals (148 controls, 119 with mandibular prognathism, and 126 with mandibular retrognathism) were screened for this case-control study. Cephalometric analysis, using Steiner parameters and "Wits" appraisal, verified skeletal relationships. Genomic DNA, extracted from gingival blood samples, was genotyped for rs1383180 using polymerase chain reaction-restriction fragment length polymorphism and validated using Sanger sequencing. Bioinformatics tools, including MUpro, iStable, DynaMut2, INPS-MD, SWISS-MODEL, ConSurf, PhD-SNPg, and Cscape, predicted the impact of the variant on protein function.

The AA genotype of rs1383180 was significantly associated with mandibular prognathism (p = 0.036) and the mutant allele (A) trended towards significance (p = 0.081). There was no association with mandibular retrognathism. Bioinformatics analysis predicted that the G > A transition may disrupt the structure and stability of EVC protein. ConSurf indicated moderate evolutionary conservation and PhD-SNPg and Cscape identified rs1383180 as pathogenic and oncogenic.

The AA genotype of rs1383180 was associated with an increased risk of skeletal Class III malocclusion due to mandibular prognathism. As this genotype may disrupt Hedgehog signaling, this pathway may be influencing mandibular development.