Introduction: Skeletal abnormalities and malocclusions have varied features that impact populations globally, impairing aesthetics and lowering life quality. The prevalence of the Skeletal Class III disease is the lowest among all angle malocclusions, with varied prevalence across nations. Environmental, genetic, and societal factors play a role in its numerous etiologies. In this study, we conducted a thorough search across the published data relating to quantitative trait loci (QTL) and the genes associated with Class III progression in humans, discussed these findings and their limitations, and proposed future directions and strategies for studying this phenotype. Methods: An inclusive search of published papers in the PubMed and Google Scholar search engines using the following terms: 1. Human skeletal Class III; 2. Genetics of Human skeletal Class III; 3. QTL mapping and gene associated with human skeletal Class III; 4. enriched skeletal Class-III-malocclusion-associated pathways. Results: Our search has found 53 genes linked with skeletal Class III malocclusion reported in humans, genes associated with epigenetics and phenomena, and the top 20 enriched pathways associated with skeletal Class III malocclusion. Conclusions: The human investigations yielded some contentious conclusions. We conducted a genome-wide association study (GWAS), an epigenetics-wide association study (EWAS), RNA-seq analysis, integrating GWAS and expression quantitative trait loci (eQTL), micro- and small-RNA, and long non-coding RNA analysis in tissues connected to skeletal Class III malocclusion phenotype in tissues connected with the skeletal phenotype. Finally, we invite regional, national, and international orthodontists and surgeons to join this effort by contributing human samples with skeletal Class III malocclusion following the accepted Helsinki ethical protocol to challenge these phenomena jointly.

This review examines a prevalent condition with multifaceted etiology encompassing genetic, environmental, and oral behavioral factors. It stands as a significant ailment impacting oral functionality, aesthetics, and quality of life. Longitudinal studies indicate that malocclusion in primary dentition may progress to permanent malocclusion. Recognizing and managing malocclusion in primary dentition is gaining prominence. The World Health Organization ranks malocclusions as the third most widespread oral health issue globally. Angle’s classification system is widely used to categorize malocclusions, with Class I occlusion considered the norm. However, its prevalence varies across populations due to genetic and examination disparities. Genetic factors, including variants in genes like MSX1, PAX9, and AXIN2, have been associated with an increased risk of Class I occlusion. This review aims to provide a comprehensive overview of clinical strategies for managing Class I occlusion and consolidate genetic insights from both human and murine populations. Additionally, genomic relationships among craniofacial genes will be assessed in individuals with Class I occlusion, along with a murine model, shedding light on phenotype–genotype associations of clinical relevance. The prevalence of Class I occlusion, its impact, and treatment approaches will be discussed, emphasizing the importance of early intervention. Additionally, the role of RNA alterations in skeletal Class I occlusion will be explored, focusing on variations in expression or structure that influence craniofacial development. Mouse models will be highlighted as crucial tools for investigating mandible size and prognathism and conducting QTL analysis to gain deeper genetic insights. This review amalgamates cellular, molecular, and clinical trait data to unravel correlations between malocclusion and Class I phenotypes.

Background: Orthodontic problems can affect vital quality of life functions, such as swallowing, speech sound production, and the aesthetic effect. Therefore, it is important to diagnose and treat these patients precisely. The main aim of this study is to introduce new classification methods for skeletal class I occlusion (SCIO) and skeletal class II malocclusion (SCIIMO) among Arab patients in Israel. We conducted hierarchical clustering to detect critical trends within malocclusion classes and applied machine learning (ML) models to predict classification outcomes. Methods: This study is based on assessing the lateral cephalometric parameters from the Center for Dentistry Research and Aesthetics based in Jatt, Israel. The study involved the encoded records of 394 Arab patients with diagnoses of SCIO/SCIIMO, according to the individualized ANB of Panagiotidis and Witt. After clustering analysis, an ML model was established by evaluating the performance of different models. Results: The clustering analysis identified three distinct clusters for each skeletal class (SCIO and SCIIMO). Among SCIO clusters, the results showed that in the second cluster, retrognathism of the mandible was less severe, as represented by a lower ANB angle. In addition, the third cluster had a lower NL-ML angle, gonial angle, SN-Ba angle, and lower ML-NSL angle compared to clusters 1 and 2. Among SCIIMO clusters, the results also showed that the second cluster has less severe retrognathism of the mandible, which is represented by a lower ANB angle and Calculated_ANB and a higher SNB angle (p < 0.05). The general ML model that included all measurements for patient classification showed a classification accuracy of 0.87 in the Random Forest and the Classification and Regression Tree models. Using ANB angle and Wits appraisal only in the ML, an accuracy of 0.78 (sensitivity = 0.80, specificity = 0.76) was achieved to classify patients as SCIO or SCIIMO. Conclusions: The clustering analysis revealed distinguished patterns that can be present within SCIO and SCIIMO patients, which can affect the diagnosis and treatment plan. In addition, the ML model can accurately diagnose SCIO/SCIIMO patients, which should improve precise diagnostics.

This study investigates the significance of skeletal transverse dimension (STD) in orthodontic therapy and its impact on occlusal relationships. The primary goal is to enhance understanding and promote the integration of transverse skeletal diagnostics into routine orthodontic assessments. To achieve this aim, the study employs a comprehensive approach, utilizing model analysis, clinical assessments, radiographic measurements, and occlusograms. The initial step involves a meticulous assessment of deficiencies in the maxilla, mainly focusing on transverse dimension issues. Various successful diagnostic methods are employed to ascertain the type and presence of these deficiencies. Furthermore, the study compares surgically assisted maxillary expansion (SARME) and orthopedic maxillary expansion (OME) in addressing skeletal transverse issues. Stability assessments and efficacy analyses are conducted to provide valuable insights into the superiority of SARME over OME. The findings reveal that proper evaluation of STD is crucial in orthodontic diagnosis, as overlooking transverse dimension issues can lead to complications such as increased masticatory muscle activity, occlusal interferences, and an elevated risk of gingival recession. Surgically assisted maxillary expansion emerges as a more stable solution than orthopedic methods. In conclusion, incorporating skeletal transverse diagnostics into routine orthodontic assessments is imperative for achieving optimal occlusal relationships and minimizing negative consequences on dentition, periodontium, and joints. The study emphasizes the significance of accurate three-dimensional assessments and recommends the consideration of SARME over OME for addressing skeletal transverse deficiencies. Finally, the Collaborative Cross (CC) mouse model is also a novel mouse model for studying complex traits. Exploring the Collaborative Cross mouse model opens avenues for future research, promising further insights into transverse skeletal issues in orthodontics.

Objectives: The correct classification of orthodontic patients is essential in individualized diagnostics and treatment planning. However, due to the complexity of the craniofacial skeleton and differences related to gender, age, and ethnicity, cephalometric analysis can be prone to errors. This multicenter, cross‐sectional study aimed to compare cephalometric measurements between skeletal class I and II in German orthodontic patients and analyze the effect of gender/age subgroups. Materials and Methods: In total, 556 German orthodontic patients were included and stratified into skeletal class I ( n = 210) and II ( n = 346), based on the individualized ANB of Panagiotidis and Witt (Calculated_ANB). Both classes presented a mean age of 13 with a range of 6.6–41 years and 5.4–53 years in classes I and II, respectively. Regarding the gender variations, most participants were females, n = 194 (56%) among class I, and n = 125 (60%) among class II. Cephalometric parameters were compared between classes and among age and gender‐specific subgroups, followed by identifying correlations and performing principal component analysis (PCA). Results: Class II patients presented a more considerable sagittal discrepancy between jaw bases than class I cases (Calculated_ANB 2.8° vs. 0.025°), a more horizontal growth pattern (Gonion angle 119° vs. 123°), and compensated inclinations of the incisors in the upper (+ 1/NL 71° vs. 68°) and lower jaw (−1/ML 84° vs. 80°). Correlations were found between sagittal, vertical, and dental cephalometric parameters, which were strongest in adult class II males. Finally, ML‐NSL angle, SNPg angle, PFH/AFH ratio, and SNB angle are related to the variations of the first four components. Conclusions: The differences in cephalometric parameters between skeletal class I and II demonstrate certain configurations in vertical, sagittal, and dental parameters, and identifying these marks precisely will enable accurate diagnosis. In addition, the variations concerning gender and age highlight the possible influence of these factors on orthodontic diagnostics and treatment planning. Future studies with equal sample sizes among subgroups must validate these findings. Finally, the PCA results highlighted that the mandible’s vertical and sagittal position has a strong influence on the diagnosis of skeletal class I/II, which highlights the importance of identifying the corresponding reference marks.

Static and functional occlusal relationships are the well-defined objectives of orthodontic therapy. To accomplish it, the jaws must be positioned in centric relation (CR)/ Central occlusion (CO) and appropriately proportioned in three space planes. Orthodontists have well-established techniques when analyzing the skeletal connection between the maxilla and mandible in both sagittal and vertical planes. Although there exist multiple analyses for the skeletal transverse dimension (STD), their inclusion in conventional orthodontic diagnosis is not widely acknowledged. Transverse tooth compensations have been visually represented in prosthodontic literature using a crosshatch arch that passes through the buccal and palatal cusps of maxillary molars, known as the Wilson curve. An inflated Wilson curve has long been seen as a prosthetic maxim, increasing the possibility of working and non-working side interferences. Research has indicated a connection between higher masticatory muscle activity and posterior occlusal contacts or interferences. When skeletal transverse issues are concealed by dental expansion, there is an elevated susceptibility to gingival recession in orthodontic patients who have a small Maxilla or constricted upper jaw. The temporomandibular joints, muscles, periodontal tissue, and airway might all suffer in a susceptible patient with a transverse insufficiency brought on by a narrow maxilla. As for orthodontists, the objective is to create skeletal connections and functional occlusion that are as near ideal as feasible. This will reduce the likelihood of occlusion-related inconsistencies exacerbating the negative consequences on the dentition, periodontium, or joints. An accurate skeletal and dental diagnostic in all three space planes is required. Our goal is to explain all approaches to enable readers to use a transverse skeletal diagnostic in their practice regardless of the technological level at their disposal. The initial step is to ascertain the kind and presence of deficiencies in the maxilla. Since fewer soft tissue alterations are caused by maxilla hypoplasia in the transverse direction, skeletal transverse dimension (STD) assessment is a more significant challenge than vertical or sagittal discrepancy assessment. Model analysis, clinical assessments, radiographic measurements, and occlusograms have all proven successful in producing accurate assessments. Most of the time, surgically assisted maxillary expansion (SARME) is reported to have higher stability than orthopedic maxillary expansion (OME). We examine and discourse on possible research opportunities using the Collaborative Cross (CC) mouse model as a substitute research model.