{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T13:26:07Z","timestamp":1784294767139,"version":"3.55.0"},"reference-count":86,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,4,29]],"date-time":"2023-04-29T00:00:00Z","timestamp":1682726400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/jcm12093212","type":"journal-article","created":{"date-parts":[[2023,5,1]],"date-time":"2023-05-01T12:10:03Z","timestamp":1682943003000},"page":"3212","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Towards Genetic Dissection of Skeletal Class III Malocclusion: A Review of Genetic Variations Underlying the Phenotype in Humans and Future Directions"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3530-1420","authenticated-orcid":false,"given":"Osayd","family":"Zohud","sequence":"first","affiliation":[{"name":"Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iqbal M.","family":"Lone","sequence":"additional","affiliation":[{"name":"Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kareem","family":"Midlej","sequence":"additional","affiliation":[{"name":"Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Awadi","family":"Obaida","sequence":"additional","affiliation":[{"name":"Center for Dentistry Research and Aesthetics, Jatt 4491800, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samir","family":"Masarwa","sequence":"additional","affiliation":[{"name":"Center for Dentistry Research and Aesthetics, Jatt 4491800, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnes","family":"Schr\u00f6der","sequence":"additional","affiliation":[{"name":"Department of Orthodontics, University Hospital of Regensburg, University of Regensburg, 93047 Regensburg, Germany"},{"name":"Institute for Clinical Microbiology and Hygiene, 93053 Regensburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5351-2526","authenticated-orcid":false,"given":"Erika C.","family":"K\u00fcchler","sequence":"additional","affiliation":[{"name":"Department of Orthodontics, University Hospital of Regensburg, University of Regensburg, 93047 Regensburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aysar","family":"Nashef","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, Baruch Padeh Medical Center, Poriya, Tabaria 1520800, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3715-1120","authenticated-orcid":false,"given":"Firas","family":"Kassem","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Meir Medical Center, Kfar Saba 4428164, Israel"},{"name":"Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vadim","family":"Reiser","sequence":"additional","affiliation":[{"name":"Department of Oral & Maxillofacial Surgery, Rabin Medical Center, Beilinson Campus, Petah Tikva 4941492, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9176-4978","authenticated-orcid":false,"given":"Gavriel","family":"Chaushu","sequence":"additional","affiliation":[{"name":"Department of Oral & Maxillofacial Surgery, Rabin Medical Center, Beilinson Campus, Petah Tikva 4941492, Israel"},{"name":"School of Dental Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Mott","sequence":"additional","affiliation":[{"name":"Department of Genetics, University College of London, London SE1 7EH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Krohn","sequence":"additional","affiliation":[{"name":"Department of Orthodontics, University Hospital of Regensburg, University of Regensburg, 93047 Regensburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Kirschneck","sequence":"additional","affiliation":[{"name":"Department of Orthodontics, University Hospital of Regensburg, University of Regensburg, 93047 Regensburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Proff","sequence":"additional","affiliation":[{"name":"Department of Orthodontics, University Hospital of Regensburg, University of Regensburg, 93047 Regensburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nezar","family":"Watted","sequence":"additional","affiliation":[{"name":"Center for Dentistry Research and Aesthetics, Jatt 4491800, Israel"},{"name":"Department of Orthodontics, Faculty of Dentistry, Arab America University, Jenin 34567, Palestine"},{"name":"Gathering for Prosperity Initiative, Jatt 4491800, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5525-206X","authenticated-orcid":false,"given":"Fuad A.","family":"Iraqi","sequence":"additional","affiliation":[{"name":"Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 6997801, Israel"},{"name":"Department of Orthodontics, University Hospital of Regensburg, University of Regensburg, 93047 Regensburg, Germany"},{"name":"Gathering for Prosperity Initiative, Jatt 4491800, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Claudino, D., and Traebert, J. 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