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Genetic factors contributing to skeletal class III malocclusion: a systematic review and meta-analysis



The present systematic review aims to report and critically assess the findings of the available scientific evidence from genetic association studies examining the genetic variants underlying skeletal class III malocclusion and its sub-phenotypes.

Material and methods

A pre-piloted protocol was registered and followed. The PubMed, Scopus, WOS, Cochrane Library, Gray Open literature, and CADTH databases were explored for genetic association studies following PICOS-based selection criteria. The research was reported in accordance with PRISMA statement and HuGE guidelines. The Q-genie tool was applied to assess the quality of genetic studies. Meta-analysis of genetic association studies was done by means of Meta-Genyo tool.


A total of 8258 articles were retrieved, of which 22 were selected for in-depth analysis. Most of the studies did not differentiate between sub-phenotypes, and the cohorts were heterogeneous regarding ethnicity. Four to five principal components of class III malocclusion explained the phenotypic variation, and gene variants at MYO1H(rs10850110), BMP3(rs1390319), GHR (rs2973015,rs6184, rs2973015), FGF7(rs372127537), FGF10(rs593307), and SNAI3(rs4287555) (p < .05) explained most of the variation across the studies, associated to vertical, horizontal, or combined skeletal discrepancies. Meta-analysis results identified a statistically significant association between risk of class III malocclusion of A allele of the FBN3 rs7351083 [OR 2.13; 95% CI 1.1–4.1; p 0.02; recessive model].


Skeletal class III is a polygenic trait substantially modulated by ethnicity. A multicentric approach should be considered in future studies to increase sample sizes, applying multivariate analysis such as PCA and cluster analysis to characterize existing sub-phenotypes warranting a deeper analysis of genetic variants contributing to skeletal class III craniofacial disharmony.

Clinical relevance

Grasping the underlying mechanisms of this pathology is critical for a fuller understanding of its etiology, allowing generation of preventive strategies, new individualized therapeutic approaches and more accurate treatment planification strategies.

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Author information




Alexandra Dehesa-Santos contributed to the study conception and design, wrote the paper, and performed the literature search and data analysis of the manuscript.

Paula Iber-Diaz contributed to the literature search and data analysis.

Alejandro Iglesias-Linares contributed to the study conception and design and wrote the paper as well as its critical revision.

Corresponding author

Correspondence to Alejandro Iglesias-Linares.

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Supplementary information

Online Resource 1.

Search strategy. (DOCX 15 kb)

Online Resource 2.

Full text excluded articles and reasons for exclusion. (DOCX 19 kb)

Online Resource 3.

Genetic variants contributing to Class III craniofacial characteristics. (PPTX 44 kb)

Online Resource 4.

Hardy-Weinberg equilibrium test for each genetic variant within eligible studies. (PPTX 700 kb)

Online Resource 5.

Egger's test Funnel Plots, sensitivity-Leave-1-out Forest plots random or fixed effects for each of the genetic variant. (PPTX 4440 kb)

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Dehesa-Santos, A., Iber-Diaz, P. & Iglesias-Linares, A. Genetic factors contributing to skeletal class III malocclusion: a systematic review and meta-analysis. Clin Oral Invest 25, 1587–1612 (2021).

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  • Skeletal class III malocclusion
  • Principal component analysis
  • Genetic factors
  • Malocclusion sub-phenotypes