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Year : 2021  |  Volume : 32  |  Issue : 3  |  Page : 399-406
Systematic review on the genetic factors associated with skeletal Class II malocclusion

1 Department of Orthodontics, Saveetha Dental College and Hospital, Chennai, Tamil Nadu, India
2 Department of Orthodontics, Rajas Dental College and Hospital, Tirunelveli, Tamil Nadu, India
3 Associate Professor, (Clinical Genetics), Centre for Cellular and Molecular Research, Saveetha Dental College and Hospital, Chennai, Tamil Nadu, India

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Date of Submission18-Jan-2020
Date of Acceptance13-Apr-2020
Date of Web Publication23-Feb-2022


Aim: The aim of this study is to review studies evaluating the role of genetics in skeletal class II malocclusion. Objective: To assess the scientific evidence associating the role of genes in skeletal class II malocclusion. Materials and Methods: A complete search across the electronic database through PubMed, Cochrane, LILACS, BMC and manual hand search of orthodontic journals were done till May 2019. The keywords for the search included: “Genetics”, “class II malocclusion”, “maxillary prognathism”, “mandibular retrognathism”. Data Collection and Analysis: Studies were selected based on PRISMA guidelines. Results: Articles were selected based on the inclusion and exclusion criteria. A total of 11 cross-sectional studies satisfied the inclusion criteria and were analyzed for the role of genes in skeletal class II malocclusion. Almost all the studies except for one revealed a positive correlation of genes with skeletal class II malocclusion. Conclusions: Out of the 11 studies included, a positive correlation of the genes with the skeletal II malocclusion was found in 10 studies. Genes FGFR2, MSX1, MATN1, MYOH1, ACTN3, GHR, KAT6B, HDAC4, AJUBA were found to be positively linked to skeletal class II malocclusion.

Keywords: Genetics, genotyping, mandibular retrognathism, maxillary prognathism, skeletal class II malocclusion

How to cite this article:
George AM, Felicita A S, Milling Tania S D, Priyadharsini J V. Systematic review on the genetic factors associated with skeletal Class II malocclusion. Indian J Dent Res 2021;32:399-406

How to cite this URL:
George AM, Felicita A S, Milling Tania S D, Priyadharsini J V. Systematic review on the genetic factors associated with skeletal Class II malocclusion. Indian J Dent Res [serial online] 2021 [cited 2022 Oct 7];32:399-406. Available from:

   Introduction Top

Etiology must be given the topmost priority in deciding the treatment of any malocclusion, for unless the factors, which have caused the deformity can be determined and removed, successful treatment is not possible says Richard A. Smith[1] stressing the significance of the knowledge of etiology. A deep understanding of the etiological factors contributing to the dentofacial variation is crucial to develop novel treatment approaches.

Skeletal class II malocclusion could be due to mandibular retrognathism, maxillary prognathism or a combination of both. The treatment modality of this skeletal malocclusion due to any of the above-mentioned scenarios is age dependant considering the growth potential of the individual, prior to which the etiology of malocclusion should be given top priority in planning the treatment and minimizing the relapse factor. Orthodontics in close association with dentofacial orthopedics can successfully treat skeletal jaw discrepancies by altering the vector of dentofacial growth and thereby, changing the phenotype of a specific morphogenetic pattern. However, the success of the treatment depends on the contribution of genes, environmental factors to the malocclusion and the potentiality of orthopedic appliances to modify the skeletal pattern. Greater the genetic contribution to malocclusion, the lesser the success rate of orthodontic and orthopedic treatment. Orthognathic surgery may be required at a later stage. The correct treatment modality should be the modification of the gene responsible for maxillary prognathism or mandibular retrognathism whichever is the cause. Though it is only a hypothetical proposal, the identification of major genes and its contribution to the skeletal discrepancy should be the first step in progressing towards this path. Genetic studies are required to clearly determine the relevant genetic markers associated with a particular skeletal or dental malocclusion. Although there has been extensive literature concerning the genetic basis of various dentofacial abnormalities and malocclusions, the literature on the genetic basis of class II malocclusion is minimal.

The objective of this article is to provide a systematic review of the evidence for the genetic influence in the skeletal class II malocclusion based on the collection of articles from PubMed, Cochrane, LILACS, and BMC.

   Materials and Methods Top

PRISMA guidelines[2] were adhered to while writing this systematic review. A survey of all articles published up to May 2019 about the role of genetics in skeletal class II malocclusion was performed by using the following databases: Pubmed, Cochrane Library, LILACS, and BMC. The keywords used to identify the studies in databases were: “Genetics”, “class II malocclusion”, “maxillary prognathism”, “mandibular retrognathism”. References from original papers and reviews were checked.

Randomized controlled trials (RCTs) and prospective or retrospective, cross-sectional studies reporting data on the role of genetics in malocclusion were included.

Duplicate reports were excluded. The titles and abstracts were screened and assessed to check for the eligibility of reports. Full articles of those abstracts that met the initial inclusion criteria were retrieved. The articles found suitable for the final review analysis were read, and relevant data were collected. Data were collected on study design, method of sample collection from the subjects, methods of assessment.

Inclusion criteria

  • Studies done on human subjects evaluating the role of genetics in skeletal class II malocclusion due to maxillary prognathism or mandibular retrognathism.
  • RCTs, prospective or retrospective, cross-sectional studies.
  • Studies with adequate statistical analysis

Exclusion criteria

  • Studies on animals
  • Case reports
  • Studies with inadequate sample size.

In total, 197 articles were identified from the search engines with the following keywords Genetics, Class II malocclusion, mandibular retrognathism, maxillary prognathism, etc.

Out of which, 51 articles resulted after the removal of duplicates and after assessing the articles for eligibility, 15 articles turned out, and again 4 articles were excluded because it failed to satisfy the inclusion criteria. Finally, 11 articles were selected for appraisal.

Characteristics of all studies analyzed were formulated for study design, study settings, participant's criteria, sample size, variable description, and outcome measurements [Table 1].
Table 1: Characteristics of articles included

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   Result Top

[Table 2] shows the PRISMA flow diagram of the various stages of the study selection process followed in this systematic review. For this review, 197 records were identified through searching of four databases and other sources, 51 articles were screened for titles and abstracts after removal of duplicates, but only 15 appeared to be potentially eligible for inclusion in the review and hence underwent full-text reading. Four articles[3],[4],[5],[6] were excluded due to the appropriate reasons mentioned in [Table 3]. Finally, 11 articles were included from 197 reports as they could fulfill the pre-defined inclusion criteria mentioned in our study.
Table 2: PRISMA 2009 Flow Diagram

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Table 3: Articles excluded from the study

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All the studies included were cross-sectional studies evaluating the association of genes in skeletal class II malocclusion. Almost all the studies revealed a positive correlation between the gene of their study and the class II malocclusion except for the study by Levy et al.[7] where he found no evidence of an association between genetic polymorphisms involving tumor necrosis factor (TNF)-a and skeletal class II malocclusion.

   Discussion Top

Nature versus nurture has been a topic of debate for many years. It's really a difficult task to decide whether one's development is completely predisposed to his gene or it's mainly influenced by the environmental factors. Nevertheless, nature has proved to take the dominating side in most cases. Dentofacial morphology, a variation of which leading to malocclusion is also determined by the genes encoded in the cell. Malocclusions compromising the function and aesthetics of an individual have multiple etiologic factors. The interactions of genetic and environmental factors may account for the variability in expression of malocclusion. Detailed knowledge of the etiological factors of the varied dentofacial morphology contributing to malocclusion plays a vital role in choosing the apt treatment and retention protocol.

Most malocclusion studies to date have focused on Class III malocclusion. Association studies have found positive correlations for mandibular prognathism and certain genes. Genetic studies for Class II and Class I malocclusion are rare.

The allelic association has been proved better than twin studies from reports evaluating genetic influence on temporomandibular disorders. Recently SNPs are most frequently searched as they affect protein expression and functioning and bring about a phenotypic change.

This systematic review was conducted in an attempt to list all the studies evaluating the genetic contribution to skeletal class II malocclusion. Finally, 11 articles were shortlisted based on certain inclusion and exclusion criteria. All the articles listed were cross-sectional, studies on humans, and allelic association studies. The samples in these studies were taken from whole blood or saliva or muscle (masseter) for the extraction of the genomic DNA. Single nucleotide polymorphisms genotyping of the respective genes was done in most cases.

Jiang et al.[8] in a 2 stage case-control study investigated the association between variations in FGFR2 and skeletal malocclusions on a sample of 895 subjects and identified FGFR2 as a skeletal malocclusion risk gene.

Gupta et al.[9] conducted a cross-sectional study on 133 subjects to find the role of human MSX1 in skeletal class II and class III. Sequencing of MSX1 gene suggested that individuals having changes from G (guanosine) with A (adenine) genotype had approximately seven times low risk for developing Class II division 1 malocclusion when compared to those alleles having GG genotype and thus, allele 'A' position on chromosome 4 (rs186861426) seems to have a protective role and this study discloses an important relationship between MSX1 gene and Class II division 1 malocclusion and Class I normal skeletal relationships.

Another case-control study[10] conducted on 152 South Indian subjects aimed to examine the association between MATN1 polymorphisms and the risk of mandibular retrognathism. Genotyping of three single nucleotide polymorphisms of the MATN1 gene (rs1149048, rs1149042, and rs1065755) was carried out using polymerase chain reaction-restriction fragment length polymorphism. The rs1149042 genotype and alleles were found to be associated with reduced risk of mandibular retrognathism. Therefore, an association between the MATN1 gene polymorphisms and mandibular retrognathism was proved.

A similar study[11] aimed at evaluating MYO1H gene polymorphisms and haplotypes as risk factors for mandibular retrognathism on a sample of 50 subjects concluded that the rs3825393 polymorphism of the MYO1H gene associated with an increased risk for mandibular retrognathism.

Brian Zebrick et al.[12] examined the genetic variation and ACTN3 expression in the masseter muscle of orthognathic surgery patients to determine genotype associations with skeletal malocclusion. In that study, it was found that ACTN3 577XX was overrepresented in skeletal class II malocclusion, suggesting a biologic influence during bone growth, ACTN3 577XX underrepresented in deep bite malocclusion, suggesting muscle differences contributing to variations in vertical facial dimensions.

Huh et al.[13] studied the heritable effects of masticatory muscles and skeletal malocclusion by evaluating the association of acetyltransferase KAT6B and deacetylase HDAC4 with skeletal malocclusions. The expressions of HDAC4 and KAT6B were significantly greater in subjects with sagittal Class III than that in Class II malocclusion.

Levy et al.[7] attempted to determine the association between the polymorphism in the TNF-a gene and skeletal class II malocclusion on a sample of 181 subjects by extracting the genomic DNA from buccal epithelial cells and found no evidence of the association between genetic polymorphisms involving TNF-a and skeletal class II malocclusion.

Cunha et al.[14] found an association between genetic variants in ACTN3 and MYO1H with craniofacial skeletal patterns in Brazilians.

Uribe et al.[15] tested for correlations of soft-tissue facial dimension variations in Class II malocclusion with genes AJUBA, HMGA2, and ADK and found a positive correlation of AJUBA with facial dimension variations.

Yamaguchi et al.[16] tried to find an association between craniofacial morphology and the P56IT variant in the growth hormone receptor gene (GHR) on 100 Japanese individuals. The population without P56IT had a significantly greater mandibular ramus length (Co-Go) than did those with P56IT. This suggests that this genotype may be associated with mandibular height growth and can be a genetic marker for it.

Similarly, Zhou et al.[17] evaluated the relationship between craniofacial morphology and GHR gene and found that GHR gene polymorphism I526L was found to be associated with mandibular height.

Genetic studies for Class II and Class I malocclusion are rare. The studies above are limited by modest sample sizes, unknown generalizability of results to populations of other ancestries, and restrictive traits that ignore the complex phenotypic spectrum of malocclusion. Nonetheless, these studies have converged to highlight that genes FGFR2, MSX1, MATN1, MYOH1, ACTN3, GHR, KAT6B, HDAC4, and AJUBA are positively linked to skeletal class II malocclusion.

Understanding the genetics underlying the dentofacial variation in patients with malocclusion is fundamental to develop preventive strategies and innovative treatment modalities that will benefit individual patients.

   Conclusions Top

Knowledge of genetic contribution to malocclusion aids in planning a targeted treatment approach and deciding the retention protocol. This systematic review on the role of genetics in skeletal class II malocclusion has clearly highlighted the positive correlation of certain genes to the malocclusion. FGFR2, MSX1, MATN1, MYOH1, ACTN3, GHR, KAT6B, HDAC4, AJUBA were found to be positively linked to skeletal class II malocclusion.

In future, advances are expected to progress beyond the discovery of genetic components of malocclusion to research facilitating the implementation of this knowledge in clinics for the susceptible ones.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

   References Top

Smith RA. The etiology of angle class II division i malocclusion. Angle Orthod 1939;9:15-9.  Back to cited text no. 1
Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M, et al.; PRISMA-P Group. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 elaboration and explanation. BMJ 2015;349:g7647.  Back to cited text no. 2
Signer-Hasler H, Neuditschko M, Koch C, Froidevaux S, Flury C, Burger D, et al. A chromosomal region on ECA13 is associated with maxillary prognathism in horses. PLoS One 2014;9:e86607.  Back to cited text no. 3
Marañón-Vásquez GA, Dantas B, Kirschneck C, Arid J, Cunha A, Ramos AGC, et al. Tooth agenesis related GLI2 and GLI3 genes may contribute to craniofacial skeletal morphology in humans. Arch Oral Biol 2019;103:12-8.  Back to cited text no. 4
Roedig JJ, Phillips BA, Morford LA, Van Sickels JE, Falcao-Alencar G, Fardo DW, et al. Comparison of BMI, AHI, and apolipoprotein E ε4 (APOE-ε4) alleles among sleep apnea patients with different skeletal classifications. J Clin Sleep Med 2014;10:397-402.  Back to cited text no. 5
Breuel W, Krause M, Schneider M, Harzer W. Genetic stretching factors in masseter muscle after orthognathic surgery. Br J Oral Maxillofac Surg 2013;51:530-5.  Back to cited text no. 6
Levy SC, Antunes LAA, Abreu JGB, Nascimento JADS, Kuntz AC, Fialho WLS, et al. Determination of TNF-a gene polymorphisms on skeletal pattern in Class II malocclusion. Braz Dent J 2019;30:152-6.  Back to cited text no. 7
Jiang Q, Mei L, Zou Y, Ding Q, Cannon RD, Chen H, et al. Genetic polymorphisms in FGFR2 underlie skeletal malocclusion. J Dent Res 2019;98:1340-7.  Back to cited text no. 8
Gupta P, Chaturvedi TP, Sharma V. Expressional analysis of MSX1 (Human) revealed its role in sagittal jaw relationship. J Clin Diagn Res 2017;11:ZC71-7.  Back to cited text no. 9
Balkhande PB, Lakkakula BVKS, Chitharanjan AB. Relationship between matrilin-1 gene polymorphisms and mandibular retrognathism. Am J Orthod Dentofacial Orthop 2018;153:255-61.  Back to cited text no. 10
Arun RM, Lakkakula BV, Chitharanjan AB. Role of myosin 1H gene polymorphisms in mandibular retrognathism. Am J Orthod Dentofacial Orthop 2016;149:699-70.  Back to cited text no. 11
Zebrick B, Teeramongkolgul T, Nicot R, Horton MJ, Raoul G, Ferri J, et al. ACTN3 R577X genotypes associate with Class II and deep bite malocclusions. Am J Orthod Dentofacial Orthop 2014;146:603-11.  Back to cited text no. 12
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. Am J Orthod Dentofacial Orthop 2013;144:568-76.  Back to cited text no. 13
Cunha A, Nelson-Filho P, Marañón-Vásquez GA, Ramos AGC, Dantas B, Sebastiani AM, et al. Genetic variants in ACTN3 and MYO1H are associated with sagittal and vertical craniofacial skeletal patterns. Arch Oral Biol 2019;97:85-90.  Back to cited text no. 14
Moreno Uribe LM, Ray A, Blanchette DR, Dawson DV, Southard TE. Phenotype-genotype correlations of facial width and height proportions in patients with Class II malocclusion. Orthod Craniofac Res 2015;18(Suppl 1):100-8.  Back to cited text no. 15
Yamaguchi T, Maki K, Shibasaki Y. Growth hormone receptor gene variant and mandibular height in the normal Japanese population. Am J Orthod Dentofacial Orthop 2001;119;650-3.  Back to cited text no. 16
Zhou J, Lu Y, Gao XH, Chen YC, Lu JJ, Bai YX, et al. The growth hormone receptor gene is associated with mandibular height in a Chinese population. J Dent Res 2005;84:1052-6.  Back to cited text no. 17

Correspondence Address:
Dr. Ashwin M George
Department of Orthodontics, Saveetha Dental College and Hospital, 162, Poonamalle High Road, Chennai, Tamil Nadu - 600 077
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijdr.IJDR_59_20

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  [Table 1], [Table 2], [Table 3]

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