Genetic etiology in mandibular prognathism: a scope review

Mandibular prognathism (MP) is a craniofacial disorder that can affect patients’ appearance, characterized by a concave profile. MP can be influenced by genetic, epigenetic and environmental factors. However, the exact pathogenesis of MP remains unclear, presenting a complex clinical challenge. We gathered information on the potential etiology of MP from sources such as PubMed, ScienceDirect and Web of Science. As a result, MP is associated with 70 genes or factors, including collagen type II alpha1 chain (COL2A1), insulin-like growth factor1 (IGF1), matrilin-1 (MATN1), Myosin 1H (MYO1H) and plexin A2 (PLXNA2). It is crucial to collect and summarize these findings to enhance our understanding of the molecular pathogenesis of both syndromic and nonsyndromic MP. Additionally, identifying gene-environment interactions and developmental mechanisms is essential in understanding the phenotypic diversity of MP. This study sheds light on the genetic etiology of MP, offering new evidence for prevention and future prospects of this condition.

Mandibular prognathism; Genetic etiology; Clinical treatment

[1] Fang H, Li P, Zhu S, Bi R. Genetic factors underlying Mandibular prognathism: insights from recent human and animal studies. Mammalian Genome. 2025; 36: 293–305.

[2] Ko JM, Suh YJ, Hong J, Paeng JY, Baek SH, Kim YH. Segregation analysis of mandibular prognathism in Korean orthognathic surgery patients and their families. The Angle Orthodontist. 2013; 83: 1027–1035.

[3] Chou ST, Wang JL, Chen SC, Pan CY, Chen CM, Tseng YC. Correlation between facial asymmetry of skeletal class III jaw relationship and morphology of the temporomandibular joint: a cone beam computed tomography study. Journal of Dental Sciences. 2023; 18: 1031–1041.

[4] Cremona M, Bister D, Sheriff M, Abela S. Quality-of-life improvement, psychosocial benefits, and patient satisfaction of patients undergoing orthognathic surgery: a summary of systematic reviews. European Journal of Orthodontics. 2022; 44: 603–613.

[5] Li C, Cai Y, Chen S, Chen F. Classification and characterization of class III malocclusion in Chinese individuals. Head & Face Medicine. 2016; 12: 31.

[6] Zohud O, Lone IM, Midlej K, Obaida A, Masarwa S, Schroeder A, et al. Towards genetic dissection of skeletal class III malocclusion: a review of genetic variations underlying the phenotype in humans and future directions. Journal of Clinical Medicine. 2023; 12: 3212.

[7] Papadopoulou AK, Koletsi D, Masucci C, Giuntini V, Franchi L, Darendeliler MA. A retrospective long-term comparison of early RME-facemask versus late Hybrid-Hyrax, alt-RAMEC and miniscrew-supported intraoral elastics in growing class III patients. International Orthodontics. 2022; 20: 100603.

[8] Hattori Y, Pai BC, Lo CC, Chou PY, Lo LJ. Comparison between one-jaw and two-jaw designs in virtual surgery planning for patients with class III malocclusion. Journal of Cranio-Maxillofacial Surgery. 2024; 52: 612–618.

[9] Li DTS, Wang R, Wong NSM, Leung YY. Postoperative stability of two common ramus osteotomy procedures for the correction of mandibular prognathism: a randomized controlled trial. Journal of Cranio-Maxillofacial Surgery. 2022; 50: 32–39.

[10] Taraji S, Atici SF, Viana G, Kusnoto B, Allareddy VS, Miloro M, et al. Novel machine learning algorithms for prediction of treatment decisions in adult patients with class III malocclusion. Journal of Oral and Maxillofacial Surgery. 2023; 81: 1391–1402.

[11] Faria-Teixeira MC, Tordera C, Salvado E Silva F, Vaz-Carneiro A, Iglesias-Linares A. Craniofacial syndromes and class III phenotype: common genotype fingerprints? A scoping review and meta-analysis. Pediatric Research. 2024; 95: 1455–1475.

[12] Zhou X, Zhang C, Yao S, Fan L, Ma L, Pan Y. Genetic architecture of non-syndromic skeletal class III malocclusion. Oral Diseases. 2023; 29: 2423–2437.

[13] Dehesa-Santos A, Faria‐Teixeira MC, Iglesias-Linares A. Skeletal class III phenotype: link between animal models and human genetics: a scoping review. Journal of Experimental Zoology Part B: Molecular and Developmental Evolution. 2024; 342: 21–44.

[14] Kajii TS, Oka A, Saito F, Mitsui J, Iida J. Whole-exome sequencing in a Japanese pedigree implicates a rare non-synonymous single-nucleotide variant in BEST3 as a candidate for mandibular prognathism. Bone. 2019; 122: 193–198.

[15] Saito F, Kajii TS, Oka A, Ikuno K, Iida J. Genome-wide association study for mandibular prognathism using microsatellite and pooled DNA method. American Journal of Orthodontics and Dentofacial Orthopedics. 2017; 152: 382–388.

[16] Kalmari A, Hosseinzadeh Colagar A, Heydari M, Arash V. Missense polymorphisms potentially involved in mandibular prognathism. Journal of Oral Biology and Craniofacial Research. 2023; 13: 453–460.

[17] Xiong X, Li S, Cai Y, Chen F. Targeted sequencing in FGF/FGFR genes and association analysis of variants for mandibular prognathism. Medicine. 2017; 96: e7240.

[18] Jiang Q, Mei L, Zou Y, Ding Q, Cannon RD, Chen H, et al. Genetic polymorphisms in FGFR2 underlie skeletal malocclusion. Journal of Dental Research. 2019; 98: 1340–1347.

[19] Guan X, Song Y, Ott J, Zhang Y, Li C, Xin T, et al. The ADAMTS1 gene is associated with familial mandibular prognathism. Journal of Dental Research. 2015; 94: 1196–1201.

[20] Kantaputra PN, Pruksametanan A, Phondee N, Hutsadaloi A, Intachai W, Kawasaki K, et al. ADAMTSL1 and mandibular prognathism. Clinical Genetics. 2019; 95: 507–515.

[21] Yao S, Zhou X, Vona B, Fan L, Zhang C, Li D, et al. Skeletal class III Malocclusion Is Associated with ADAMTS2 variants and reduced expression in a familial case. International Journal of Molecular Sciences. 2022; 23: 10673.

[22] Perillo L, Monsurrò A, Bonci E, Torella A, Mutarelli M, Nigro V. Genetic association of ARHGAP21 gene variant with mandibular prognathism. Journal of Dental Research. 2015; 94: 569–576.

[23] Genno PG, Nemer GM, Zein Eddine SB, Macari AT, Ghafari JG. Three novel genes tied to mandibular prognathism in eastern Mediterranean families. American Journal of Orthodontics and Dentofacial Orthopedics. 2019; 156: 104–112.e3.

[24] Ardani IGAW, Budipramana M, Rachmawati E, Nugraha AP, Ardana IKKG, Budhy TI, et al. COL1A1 and FGFR2 single-nucleotide polymorphisms found in class II and class III skeletal malocclusions in Javanese population. European Journal of Dentistry. 2023; 17: 183–190.

[25] Frazier-Bowers S, Rincon-Rodriguez R, Zhou J, Alexander K, Lange E. Evidence of linkage in a Hispanic cohort with a class III dentofacial phenotype. Journal of Dental Research. 2009; 88: 56–60.

[26] Najafi S, Hashemi-Gorji F, Roudgari H, Goudarzi M, Jafarzadegan AM, Sheykhbahaei N. Genetic change investigation in DOCK1 gene in an Iranian family with sign and symptoms of temporomandibular joint disorder (TMD). Clinical Oral Investigations. 2024; 28: 432.

[27] Han X, Xiong X, Shi X, Chen F, Li Y. Targeted sequencing of NOTCH signaling pathway genes and association analysis of variants correlated with mandibular prognathism. Head & Face Medicine. 2021; 17: 17.

[28] Xue F, Wong R, Rabie AB. Identification of SNP markers on 1p36 and association analysis of EPB41 with mandibular prognathism in a Chinese population. Archives of Oral Biology. 2010; 55: 867–872.

[29] Rao C, Guan B, Luo D, Deng Q, Peng Q, Lin Z, et al. Identification of pathogenic variants of ERLEC1 in individuals with class III malocclusion by exome sequencing. Human Mutation. 2020; 41: 1435–1446.

[30] Li Q, Zhang F, Li X, Chen F. Genome scan for locus involved in mandibular prognathism in pedigrees from China. PLOS ONE. 2010; 5: e12678.

[31] Chen F, Li Q, Gu M, Li X, Yu J, Zhang YB. Identification of a mutation in FGF23 involved in mandibular prognathism. Scientific Reports. 2015; 5:11250.

[32] Rodrigues AS, Teixeira EC, Antunes LS, Nelson-Filho P, Cunha AS, Levy SC, et al. Association between craniofacial morphological patterns and tooth agenesis-related genes. Progress in Orthodontics. 2020; 21: 9.

[33] Shi H, Yang J, Guo Q, Zhang M. Clinical assessment and FGFR2 mutation analysis in a Chinese family with Crouzon syndrome: a case report. Medicine. 2021; 100: e24991.

[34] Sharda S, Panigrahi I, Gupta K, Singhi S, Kumar R. A newborn with acanthosis nigricans: can it be Crouzon syndrome with acanthosis nigricans? Pediatric Dermatology. 2010; 27: 43–47.

[35] Breuel W, Krause M, Schneider M, Harzer W. Genetic stretching factors in masseter muscle after orthognathic surgery. British Journal of Oral and Maxillofacial Surgery. 2013; 51: 530–535.

[36] Tunasoylu B, Unuvar YA, Erdogdu IH. Investigation of a genetic association of a class III skeletal pattern. Australasian Orthodontic Journal. 2022; 38: 162–172.

[37] Marañón-Vásquez GA, Dantas B, Kirschneck C, Arid J, Cunha A, Ramos AGDC, et al. Tooth agenesis-related GLI2 and GLI3 genes may contribute to craniofacial skeletal morphology in humans. Archives of Oral Biology. 2019; 103: 12–18.

[38] Huh A, Horton MJ, Cuenco KT, Raoul G, Rowlerson AM, Ferri J, et al. Epigenetic influence of KAT6B and HDAC4 in the development of skeletal malocclusion. American Journal of Orthodontics and Dentofacial Orthopedics. 2013; 144: 568–576.

[39] Yamaguchi T, Park SB, Narita A, Maki K, Inoue I. Genome-wide linkage analysis of mandibular prognathism in Korean and Japanese patients. Journal of Dental Research. 2005; 84: 255–259.

[40] Li Q, Li X, Zhang F, Chen F. The identification of a novel locus for mandibular prognathism in the Han Chinese population. Journal of Dental Research. 2011; 90: 53–57.

[41] Laviana A, Thahar B, Melani A, Mardiati E, Putri L, Zakyah AD. Role of matrilin-1 (MATN1) polymorphism in class III skeletal malocclusion with mandibular prognathism in Deutero-Malay race: a case-control study. Egyptian Journal of Medical Human Genetics. 2021; 22: 1–7.

[42] Milosevic O, Nikolic N, Carkic J, Juloski J, Vucic L, Glisic B, et al. Single nucleotide polymorphisms MYO1H 1001 C>T SNP (rs3825393) is a strong risk factor for mandibular prognathism. American Journal of Orthodontics and Dentofacial Orthopedics. 2022; 162: e246–e251.

[43] Küchler EC, Reis CLB, Carelli J, Scariot R, Nelson-Filho P, Coletta RD, et al. Potential interactions among single nucleotide polymorphisms in bone- and cartilage-related genes in skeletal malocclusions. Orthodontics & Craniofacial Research. 2021; 24: 277–287.

[44] da Fontoura CS, Miller SF, Wehby GL, Amendt BA, Holton NE, Southard TE, et al. Candidate gene analyses of skeletal variation in malocclusion. Journal of Dental Research. 2015; 94: 913–920.

[45] Mathur A, Negi S, Tripathy S, Aggarwal S, Amekpor F, Mehta V. Oral manifestations of Nance Horan syndrome: a systematic review of case reports. Oral Oncology Reports. 2024; 11: 100612.

[46] Ashrafzadeh F, Sadrnabavi A, Akhondian J, Beiraghi Toosi M, Mohammadi M, Hassanpour K. Angelman syndrome: a case report. Iranian Journal of Child Neurology. 2016; 10: 86–89.

[47] Lavezzi AM, Casale V, Oneda R, Gioventu S, Matturri L, Farronato G. Obstructive sleep apnea syndrome (OSAS) in children with class III malocclusion: involvement of the PHOX2B gene. Sleep and Breathing. 2013; 17: 1275–1280.

[48] Nguyen T, Phillips C, Frazier-Bower S, Wright T. Craniofacial variations in the tricho-dento-osseous syndrome. Clinical Genetics. 2013; 83: 375–379.

[49] Cıvak T, Trakyali G, Varol A. Orthognathic treatment in Greig cephalopolysyndactyly syndrome: a case report. Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology. 2019; 31: 327–332.

[50] Gursoy S, Hazan F, Kaderli B, Mese T, Tukun A. Orodental, facial and clinical features of mutation-positive Noonan syndrome: a monocentric study. Journal of Clinical Pediatric Dentistry. 2020; 44: 262–267.

[51] Schwarze UY, Dobsak T, Gruber R, Bookstein FL. Anatomical similarity between the Sost-knockout mouse and sclerosteosis in humans. The Anatomical Record. 2020; 303: 2295–2308.

[52] Maharjan B, Singh J, Mishra SC, Neupane S. General anesthesia in a patient with cleidocranial dysplasia: a case report. JCA Advances. 2024; 1: 100036.

[53] Dobrzynski W, Stawinska-Dudek J, Moryto N, Lipka D, Mikulewicz M. Floating-harbor syndrome: a systematic literature review and case report. Journal of Clinical Medicine. 2024; 13: 3435.

[54] Cheng L, Zhang Y, Ding Y, Yuan Z, Han X. The clinical and genetic findings in a Chinese family with Axenfeld-Rieger syndrome. Heliyon. 2022; 8: e12543.

[55] Lamazza L, Messina A, D’Ambrosio F, Spink M, De Biase A. Craniometaphyseal dysplasia: a case report. Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology. 2009; 107: e23–e27.

[56] Borborema dos Santos VD, de Assis GM, da Silva JSP, Germano AR. Partial glossectomy in a patient carrier of Beckwith-Wiedemann syndrome: presentation of a case. Revista Española de Cirugía Oral y Maxilofacial. 2015; 37: 202–206.

[57] Oka A, Inubushi T, Kani R, Yamashiro T. Orthodontic management of severe hypodontia and impacted maxillary second molars in a patient with Sotos syndrome. The Cleft Palate-Craniofacial Journal. 2025; 62: 164–172.

[58] Shioyasono R, Yoshinaga K, Shioyasono A, Ito A, Watanabe K, Hiasa M, et al. Nonsurgical orthodontic treatment for a patient with Sotos syndrome. American Journal of Orthodontics and Dentofacial Orthopedics. 2023; 163: 426–442.

[59] Li JY, Chen J, Liu J, Zhang SZ. Simultaneous rectal neuroendocrine tumors and pituitary adenoma: a case report and review of literature. World Journal of Gastroenterology. 2023; 29: 5082–5090.

[60] Junn A, Dinis J, Lu X, Forte AJ, Mozaffari MA, Phillips S, et al. Facial dysmorphology in Saethre-Chotzen syndrome. Journal of Craniofacial Surgery. 2021; 32: 2660–2665.

[61] Sciote JJ, Raoul G, Ferri J, Close J, Horton MJ, Rowlerson A. Masseter function and skeletal malocclusion. Journal of Stomatology, Oral and Maxillofacial Surgery. 2013; 114: 79–85.

[62] Park HJ, Ahn SJ, Jang J, Kim SJ, Park YG, Kim KA. Genetic effect of single nucleotide polymorphisms in growth hormone receptor gene on the risk of non-syndromic mandibular prognathism in the Korean population. Orthodontics & Craniofacial Research. 2022; 25: 437–446.

[63] Bierley K, Antonarakis GS. Lateral cephalometric characteristics in individuals with down syndrome compared to non-syndromic controls: a meta-analysis. Journal of Stomatology, Oral and Maxillofacial Surgery. 2023; 124: 101407.

[64] Tian Y, Li M, Yang J, Chen H, Lu D. Preimplantation genetic testing in the current era, a review. Archives of Gynecology and Obstetrics. 2024; 309: 1787–1799.