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

IF 0.9 Q4 GENETICS & HEREDITY

Gene Reports Pub Date : 2025-09-30 DOI:10.1016/j.genrep.2025.102347

Katarzyna Chojnacka , Marcin Mikulewicz

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引用次数: 0

Abstract

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.

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骨骼错咬合的基因组结构：对精确正畸的影响-叙述性回顾

遗传变异，特别是单核苷酸多态性（snp），通过控制形态发生的核心途径（如FGF/FGFR、WNT/β-catenin、TGF-β/BMP和GH/IGF轴）与颅面生长、牙槽发育和骨骼重塑有关。等位基因频率和效应大小的种族间差异表明了特定于祖先的结构。在全基因组关联研究（GWAS）和候选基因分析中，已经报道了与骨骼II/III类错牙合相关的多个候选基因和位点，包括GHR/IGF1、FGFR2、RUNX2、WNT3A、MSX1和GLI2的信号。目的整理和批判性评估目前骨骼错颌的遗传证据，并确定与精确正畸护理相关的功能支持的snp子集。考虑到队列异质性和祖先特异性效应，当复制（如有）、生物学合理性和临床相关性趋同时，标记为高置信度的位点被优先考虑。在这里，功能性SNP是指具有实验或表达证据的变异，可以对基因调控、蛋白质功能或发育产生生物学效应。方法综述与PubMed/Scopus的结构化检索（上次检索于2025年5月5日）。采用了两种互补的方法：(i)将基因型、表型、推测机制、合子性和参考文献链接在一起的注释表；（ii）按祖先（亚洲人、欧洲人、混血儿）分层的等位基因表型基质。结果在筛选的大约95个报道的snp中，38个符合预定义的标准（包括可用的复制，与颅面发育的功能相关性，以及与前突和/或上颌缺陷的临床相关性）。几个基因座的复制仍然有限。结果集为风险分层提供了实用基础，而不是确定性预测。从这38个snp的高置信度集中，我们选择了一个说明性的11个snp子集来原型PRS-Ortho v1。结论：本文综合了70多项同行评议研究的证据，提出了38个功能支持的snp，目前与颅面生长最相关。这些数据支持了精确正畸的个性化诊断、治疗计划和预后，同时强调了在常规临床试验之前进行多民族复制和前瞻性评估的必要性。提供了一个11-SNP子集（PRS-Ortho v1）作为说说性非加权评分的原型。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Gene Reports Biochemistry, Genetics and Molecular Biology-Genetics

CiteScore

3.30

自引率

7.70%

发文量

246

审稿时长

49 days

期刊介绍： Gene Reports publishes papers that focus on the regulation, expression, function and evolution of genes in all biological contexts, including all prokaryotic and eukaryotic organisms, as well as viruses. Gene Reports strives to be a very diverse journal and topics in all fields will be considered for publication. Although not limited to the following, some general topics include: DNA Organization, Replication & Evolution -Focus on genomic DNA (chromosomal organization, comparative genomics, DNA replication, DNA repair, mobile DNA, mitochondrial DNA, chloroplast DNA). Expression & Function - Focus on functional RNAs (microRNAs, tRNAs, rRNAs, mRNA splicing, alternative polyadenylation) Regulation - Focus on processes that mediate gene-read out (epigenetics, chromatin, histone code, transcription, translation, protein degradation). Cell Signaling - Focus on mechanisms that control information flow into the nucleus to control gene expression (kinase and phosphatase pathways controlled by extra-cellular ligands, Wnt, Notch, TGFbeta/BMPs, FGFs, IGFs etc.) Profiling of gene expression and genetic variation - Focus on high throughput approaches (e.g., DeepSeq, ChIP-Seq, Affymetrix microarrays, proteomics) that define gene regulatory circuitry, molecular pathways and protein/protein networks. Genetics - Focus on development in model organisms (e.g., mouse, frog, fruit fly, worm), human genetic variation, population genetics, as well as agricultural and veterinary genetics. Molecular Pathology & Regenerative Medicine - Focus on the deregulation of molecular processes in human diseases and mechanisms supporting regeneration of tissues through pluripotent or multipotent stem cells.