Genomic architecture of skeletal malocclusions: Implications for precision orthodontics - Narrative review

Background

Genetic variants, particularly single-nucleotide polymorphisms (SNPs), have been linked to craniofacial growth, dentoalveolar development, and skeletal remodeling through core pathways that govern morphogenesis (e.g., FGF/FGFR, WNT/β-catenin, TGF-β/BMP, and the GH/IGF axis). Interethnic differences in allele frequencies and effect sizes indicate ancestry-specific architecture. Multiple candidate genes and loci related to skeletal Class II/III malocclusion have been reported across genome-wide association studies (GWAS) and candidate-gene analyses, including signals at GHR/IGF1, FGFR2, RUNX2, WNT3A, MSX1, and GLI2.

Aim

To collate and critically appraise current genetic evidence on skeletal malocclusions and to identify a functionally supported subset of SNPs relevant to precision orthodontic care. Given cohort heterogeneity and ancestry-specific effects, loci labeled as higher-confidence were prioritized when replication (where available), biological plausibility, and clinical association converged. Here, a functional SNP denotes a variant with experimental or expression evidence for a biological effect on gene regulation, protein function, or development.

Methods

Narrative review with a structured search of PubMed/Scopus (last search May 5, 2025). Two complementary approaches were applied: (i) an annotation table linking genotype, phenotype, putative mechanism, zygosity, and references; and (ii) an allele-phenotype matrix stratified by ancestry (Asian, European, admixed).

Results

Of approximately 95 reported SNPs screened, 38 met the predefined criteria (including replication where available, functional relevance to craniofacial development, and clinical association with prognathism and/or maxillary deficiency). Replication remains limited for several loci. The resulting set provides a pragmatic basis for risk stratification, not deterministic prediction. From this 38-SNP higher-confidence set, we selected an illustrative 11-SNP subset to prototype PRS-Ortho v1.

Conclusions

This narrative review synthesizes evidence from over 70 peer-reviewed studies and presents 38 functionally supported SNPs currently most relevant to craniofacial growth. These data support the personalization of diagnosis, treatment planning, and prognosis in precision orthodontics, while underscoring the need for multi-ethnic replication and prospective evaluation before routine clinical testing. An 11-SNP subset (PRS-Ortho v1) is provided as a prototype for illustrative, unweighted scoring.