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Genetics of malocclusion: A review

Article · February 2020

DOI: 10.31436/ijohs.v1i1.2

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International Journal of Orofacial and Health Sciences (2020) 1(1)

REVIEW ARTICLE

Genetics of malocclusion: A review

Khairani Idah Mokhtar1*, Noraini Abu Bakar2, Aisyah Hanani Bt Md Ali @ Tahir3

1
Department of Fundamental Dental and Medical Sciences, Kulliyyah of Dentistry, IIUM Kuantan
Campus.
2
Department of Orthodontics, Kulliyyah of Dentistry, IIUM Kuantan Campus,
3
Department of Biomedical Science, Kulliyyah of Allied Health Sciences, IIUM Kuantan Campus.

Abstract

Malocclusion is one of the most common craniofacial problems observed worldwide.

Affected individuals suffer not only from aesthetic concerns but also from functional
problems, such as with mastication and pronunciation. The prevalence of malocclusion in
East Asians is higher than in other races. Reports have shown besides environmental
factors, there is association between certain types of malocclusion with specific genes.
Positive association of mandibular prognathism has been implicated to genes such as
Matrilin-1; while mutation in DUSP6 has also been shown to contribute to the incidence of
malocclusion. This review aimed to briefly discuss the involvement of other additional genes
such as MYO1H and PAX9 in the incidence of malocclusion as observed from our local
institution.

Keywords: malocclusion, genes

*Corresponding Author
Email address: [email protected]
Tel: +6013-927 8779

Introduction Nonetheless, the condition of

malocclusion may lead to distorted facial
Malocclusion is one of the most common appearance, limited masticatory function,
dental problems in mankind, together increased risk of dental trauma and
with dental caries, gingival disease and compromise the quality of life (Claudino
dental fluorosis (Dhar et al., 2007). A et al., 2013).
malocclusion is defined as an irregularity
Classification of skeletal and dental
of the teeth or a mal-relationship of the
malocclusion
dental arches beyond the range of what
is accepted as normal (Walther et al., The deviations from normal occlusion can
1994). Malocclusion should not be be presented clinically from skeletal
considered as abnormal or pathological, and/or dental. Skeletal discrepancy is
instead as a variation of occlusion in a caused by the distortion of the proper
continuous multifactorial trait (Nishio et mandibular and/or maxillary growth during
al., 2016). fetal development (Joshi et al., 2014). This
can occur in any three plan of space:

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International Journal of Orofacial and Health Sciences (2020) 1(1)

anteroposterior, vertical and transverse mesio-buccal cusp of the maxillary first

(Alhammadi, 2019). Salzmann in 1950 molar.
was among the first to classify to the
On the other hand, Class III molar
underlying skeletal structure into Class I,
relationship is classified when the molar
Class II (convex profile) and Class III
relationship shows the buccal groove of
(concave profile).
the mandibular first molar mesially
Dental malocclusion may be classified positioned to the mesio-buccal cusp of the
according to several classifications. One maxillary first molar when the teeth are in
classification is by British Standard occlusion.
Institution (BSI, 1983) classifying the
Prevalence of malocclusion
occlusion according to the incisor
relationship, into Class I, Class II Division The prevalence of dental malocclusion in
1, Class II Division 2 and Class III. Class I East Asians especially Class III is higher
incisor relationship is when the mandibular than in other races (Soh et al., 2005).
incisors edges occlude with or lie This has been supported by a finding by
immediately below the cingulum plateau of Chu et al. (2007), which compared their
the maxillary central incisors. Class II study with those from surveys of young
incisor relationship is subdivided into Caucasians, Africans and Asians. This
division 1 and division 2 according to the study showed that the prevalence of
inclination of the upper incisors. Class II Class I malocclusion in Chinese adults
division 1 occurs when the maxillary was higher than that in Caucasian adults
central incisors are proclined (or with (48% versus 23%), but was similar to
average inclination) with an increased that of Asian (48%) or African (50%)
overjet. Whereas, class II subdivision 2 young adults. The prevalence of Class III
happens when the maxillary central malocclusion in Chinese and in Asian
incisors are retroclined and the overjet can adults is higher than that in African adults
be minimum or maybe increased. Class III (20% versus 14%). Although Class II
is when the mandibular incisors edges lie malocclusion is less common in the
anterior to the cingulum plateau of the Chinese young adults, a study using
upper central incisors with the overjet peer assessment rating index reported
reduced or reversed. that Class II malocclusion being more
severe than Class I or III malocclusion in
Angle classification used occlusal
young Asian males (Soh et al., 2005).
relationship of the first molar to classify
While in the Northern part of Saudi
type of malocclusion into three classes
Arabia, Class I malocclusion was
that are Class I, Class II and Class III
dominant, followed by Class II and Class
(Weinberger, 1993). Class I molar
III, respectively (Alajlan et al., 2019).
relationship is characterized by normal
mesio-distal relation of the jaws and Hardy et al. (2012) through his
dental arches, as indicated by the normal meta-analysis study reported that,
locking on eruption of the first permanent Chinese from Hong Kong and Malaysian
molars, at least in their mesio-distal showed a relatively higher prevalence of
relations, though one or more may be in Angle Class III malocclusion. In addition,
buccal or lingual occlusion. Class II molar Indian populations showed a relatively
relationship can be explained by the molar lower prevalence as compared to other
relationship shows the buccal groove of races (Hardy et al., 2012). Our own
the mandibular first molar distally demographic study showed that Class III
positioned when in occlusion with the

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International Journal of Orofacial and Health Sciences (2020) 1(1)

(according to BSI Incisor Classification) and PLXNA, located within the locus
represents the majority of malocclusion 1p22-p36, while genes COL2A1, TGFB3,
cases observed in our local setting, and LTBP2 within the 12q13-q24 locus.
whereby Malays constitute the highest MATRILIN-1 is a cartilage matrix protein
number of orthodontic patients followed and its polymorphism has been shown to
by Chinese and Indians (Ismail et al., be associated with mandibular
2017). The prevalence data indicated prognathism in Korean population (Jang
that the occurrence of different types of et al., 2010). Genotyping results showed
malocclusion varies according to that the Matrilin-1 polymorphism
geographical location. haplotype TGC had a pronounced risk
effect for mandibular prognathism
Genetics and malocclusion
compared with controls which suggest
Aetiologically, skeletal malocclusions that polymorphisms in Matrilin-1 could be
arise from skeletal disharmonies. Thus, it used as a marker for genetic
is essential to have a good susceptibility to mandibular prognathism.
understanding of the skeletal growth in
The mutation in DUSP6 has also
general. In orthodontics, one of the most
been identified in cases of malocclusion
challenging aspects in treating patients is
and reinforces that the 12q22-q23 region
predicting their craniofacial growth
is biologically relevant to craniofacial
patterns. In this respect, it is important to
development and may be genetically
understand how genetic factors and their
linked to the Class III malocclusion
interactions with environmental factors
(Nikopensius et al., 2013). Very recently,
affect facial growth in a particular
Nowrin et al. (2019) detected a missense
individual.
mutation in EXON 3 of DUSP6 gene in
Study of the aetiology of three members of a Malaysian Malay
malocclusion is a complex subject since family with Class III malocclusion. This
both genetic and environmental factors study further acknowledged the
may affect craniofacial development importance of DUSP6 gene in skeletal
(Mossey, 2014). Several studies have functions (Nowrin et al., 2019).
shown that there is a strong link of
With the advancement of
malocclusion especially skeletal
dentofacial phenotyping and the
malocclusion Class III or mandibular
availability of large-scale genomic data
prognathism (MP), with both genetic as
analysis, the fundamental aspect of
well as environmental factors (Jena et
genetic mechanism which underlies the
al., 2005; Chaturvedi et al., 2011;
developmental process of craniofacial
Hartsfield et al., 2012).
complex is unravelled. Additionally,
The relative genetic contribution available genetic analysis such as
to Class III malocclusion has been the linkage analysis, whole exome
subject of interest of many researchers. sequencing, polymorphism or mutational
Some evidence has been found analysis has enabled genetic association
suggesting that genetic factors contribute study to be performed on malocclusion
to the malocclusion susceptibility. In a cases, hence broadened the knowledge
review article, Moreno et al. (2015) on the involvement of certain genes with
mentioned that association studies have the incidence of malocclusion.
found positive correlations for mandibular
prognathism and genes EPB41, SSX21P

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International Journal of Orofacial and Health Sciences (2020) 1(1)

Pax9 Genes have an association with Class II/Division

2 malocclusion with hypodontia except the
Alterations in genes which are important
third molar (Wall et al., 2009). Ghergie et
during the process of craniofacial
al., (2013a) also found association
development have been associated with
between PAX9 SNP (rs8004560) with
the incidence of craniofacial abnormalities.
Class I malocclusion patients. We have
Paired Box 9 gene (PAX9 gene) located at
performed sequencing analysis on
chromosome 14 (locus 14q13.3) is a gene
patients with Class II skeletal base
family which is responsible in tooth as well
malocclusion for PAX9 SNP (rs8004560).
as skeletal development (Ghergie et al.,
However, no significant association of
2013). Anne et al., (2015) claimed that
PAX9 SNP (rs8004560) with Class II
PAX9 gene regulates cell proliferation,
skeletal base was observed from our local
migration and determination in multiple
population (Saad et al., 2018). This might
neural crest-derived lineages, such as
be due to small number of samples
cardiac, sensory, and enteric neural crest,
recruited in our study.
pigment cells, glia, craniofacial skeleton
and teeth, or in organs developing in close Myo1H Genes
relationship with the neural crest such as
Another gene which has been shown to
the thymus and parathyroids. PAX9 gene
be associated with malocclusion is
is a protein encoding gene that encodes
MYO1H. MYO1H, located at 12q24.11 is a
the transcription factor that is important for
class 1 myosin that is in a different protein
craniofacial and dental development (Seo
grouping than the myosin heavy chain
et al., 2013). Krivicka-Uzkurele et al.,
isoforms found in the skeletal muscle
(2016) stated PAX9 gene is expressed in
sacromeres, which are the basis of fibre
the developing facial processes and
typing. Myosin is superfamily of motor
influence the formation of lower face.
proteins that involve in generating force
Kavitha et al., (2010) found that PAX9
and movement along actin filaments
gene has 4 exons which are highly
(Mooseker and Cheney, 1995). Class 1
conserved in human being. Mutated PAX9
myosin is necessary for cell motility;
gene is frequently associated with
phagocytosis and vesicle transport
oligodontia or hypodontia as well as Class
(Rowlerson et al., 2005). Myosin heavy
II/Division 2 malocclusion (Ghergie et al.,
chain isoforms was revealed to be found
2013a). Animal studies conducted by
in the masseter muscle via
Peter et al., (1998) and Nakatomi et al.,
immunohistochemical staining and gene
(2010) found that mutated or absence of
expression studies (Arun et al., 2016).
PAX9 gene shown poor development of
Few studies suggest that muscle affect
skeletal and odontogenesis with lack of
the skeletal growth during embryonic
coronoid process formation. Peter et al.,
stage, postnatal stage, and homeostatic
(1998) added this particular gene was
relationship in adult and aging process
highly expressed at the region of
(Brotto, 2015). Therefore, genetic
pharyngeal pouches, mesenchyme of
alteration in genes responsible for muscle
nasal processes, maxillary and
function will also affect the skeletal
mandibular arches, as well as at the area
growth. In a recent article, Sun et al.
of developing tooth buds hence supporting
(2018) have shown that the expression of
the importance of PAX9 in craniofacial,
MYO1H orthologous genes were detected
tooth and skeletal development.
at mandibular jaw of zebrafish model,
Polymorphism in PAX9 gene; SNP whereby jaw cartilage defects were
marker rs8004560, has been suggested to demonstrated in the MYO1H knockdown

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International Journal of Orofacial and Health Sciences (2020) 1(1)

model. These developmental and been done in other parts of the world. As
functional studies strongly demonstrate far as we are aware, scanty data
the importance of MYO1H gene for proper regarding dental malocclusion and its
jaw growth and development and its genetic analysis is available from our
contribution towards the pathogenesis of local population (Esa et al., 2001). Thus,
mandibular prognathism and mandibular we hope that the ongoing studies carried
retrognathism in human (Arun et al., 2016; out in this institution could provide new
Sun et al., 2018). scientific information for the betterment
of the knowledge in the management
Tassopoulou-Fishell et al. (2013)
and treatment of malocclusion in this
reported significant association between
population. This could attribute to
MYO1H SNP (rs10850110) with
clinicians and researcher in the field of
mandibular prognathism patients whom
craniofacial research.
are mostly Caucasian. Ghergie et al.
(2013b) also performed single nucleotide Acknowledgement
polymorphism analysis of MYO1H gene
We would like to acknowledge IIUM
(rs10850110) on malocclusion Class I, II
Research Initiative Grant (RIGS 15-045-
and III from Romanian population. Their
0045) for the financial support and staff of
study also detected association of MYO1H
Department of Orthodontics and Center
SNP (rs10850110) allele and genotypes
Research and Animal Facility (CREAM)
with different malocclusion cases. Arun et
for their assistance.
al. (2016) studied genetic association by
performing PCR-RFLP methods on three References
SNP markers of MYO1H on mandibular
Alajlan, S. S., Alsaleh, M. K., Alshammari, A. F.,
retrognathism cases. These markers Alharbi, S. M., Alshammari, A. K.,
include rs10850110, rs11611277 and Alshammari, R. R. (2019). The prevalence of
rs3825393. The SNP rs3825393 showed malocclusion and orthodontic treatment need
a statistically significant association with of school children in Northern Saudi Arabia.
Journal of Orthodontics Science. 8 (1),10
mandibular retrognathism, while no
Alhammadi, M. S. (2019). Dentoalveolar
association was detected in other two compensation in different anterioposterior
polymorphism markers with mandibular and vertical skeletal malocclusions. Journal
retrognathism (Arun et al., 2016). Due to of Clinical & Experimental Dentistry.
these findings, we also initiated a 11(8):e745-53.
Anne H, Monsoro. B. (2015), PAX transcription
preliminary analysis of MYO1H single factors in neural crest development. Seminar
nucleotide polymorphism of rs10850110 in Cell & Development Biology, 44, 87-96.
on mandibular prognathism cases, but no Arun R. M., Lakkakula B. V. K. S., Chitharanjan
significant association was observed. A. B. (2016). Role of myosin 1h gene
polymorphisms in mandibular retrognathism.
Again, small sample size might contribute
American Journal of Orthodontics &
to this finding (Yahya et al., 2018). Thus, Dentofacial Orthopedics, 149, 699-704
we are proposing for larger number of Brotto M. & Bonewald L. (2015). Bone and
samples to be recruited for future genetic muscle: interactions beyond mechanical.
association study. In addition, the criteria Bone, 80: 109-114
Chaturvedi, S., Kamath, P., & Prasad, R. (2011).
for inclusion and exclusion to fulfil the Class III malocclusion. Role of nature and
exact classification of the malocclusion nurture. Virtual Journal of Orthodontics, 9(1),
must be followed strictly. 1-10.
Chu, C. H., Choy, B. H., & Lo, E. C. (2009).
To date, most of the genetic Occlusion and orthodontic treatment demand
studies looking into the polymorphism of among Chinese young adults in Hong
these genes with malocclusion have

8
International Journal of Orofacial and Health Sciences (2020) 1(1)

Kong. Oral Health & Preventive disorder with long-life morbidity. Journal of
Dentistry, 7(1), 83. Clinical Medicine Research. 6 (6):399-408.
Claudino, D., & Traebert, J. (2013). Malocclusion, Kavitha B, Priyadharshini V,
dental aesthetic self-perception and quality of Sivapathasundharam, B, Saraswathi TR (2010).
life in a 18 to 21 year-old population: a cross Role of genes in oro-dental diseases. Indian
section study. BMC Oral Health, 13(1), 1. Journal of Dental Res, 21(2): 270-274. Krivicka-
Dhar, V., Jain, A., Dyke, T. E.V., Kohli, A. (2007). Uzkurele, B., Pilmane, M. (2016).
Prevalence of gingival diseases, Expression of interferon regulatory factor 6,
malocclusion and fluorosis in school-going muslce segment homeobox 1, paired box gene
children of rural areas in Udaipur district. 9, homeobox b3, and related to tyroxine kinases
Journal of Indian Society of Pedodontics & in human cleft-affected tissue. Journal of
Preventive Dentistry. 25,103-105. Orofacial Sciences, 8(1),
Esa, R., Razak, I. A., & Allister, J. H. (2001). 59-65.
Epidemiology of malocclusion and Mooseker M.S., Cheney R.E. (1995).
orthodontic treatment need of 12-13-year-old Unconventional myosins. Annual Review of
Malaysian schoolchildren. Community Dental Cell Review Biology, 11:633-75
Health, 18(1), 31-36. Moreno Uribe L.M., Miller S.F. (2015). Genetics
Ghergie, M., Festila, D., Lupan, I., Popescu, O., & of the dentofacial variation in human
Kelemen, B. (2013a). Testing the association malocclusion. Orthodontics & Craniofacial
between orthodonthic Classes I, II, III and Research, 18(1), 91-99.
SNPs (rs731236, rs8004560, rs731236) in a Morford, L. A., Wall, M. D., Morrison, M. W., Kula,
Romanian clinical sample. Annals of the K. S., & Hartsfield Jr, J. K. (2010).
Romanian Society for Cell Biology, 18(2), 43- Association analysis of class-II Division-2
51. (CII/D2) with PAX9 and MSX1. Journal of
Ghergie, M., Feştilă, D., Kelemen, B., & Lupan, I. Dental Research, 89(Special Issue).
(2013b). Myo1H gene single nucleotide Mossey, P. A. (2014). The heritability of
polymorphism rs10850110 and the risk of malocclusion: part 1—genetics, principles
malocclusion in the Romanian population. and terminology. British Journal of
Acta Medica Transilvanica, 18(4),281-284. Orthodontics.
Hardy, D. K., Cubas, Y. P., & Orellana, M. F. Nakatomi, M., Wang, X. P., Key, D., Lund, J. J.,
(2012). Prevalence of angle class III Turbe-Doan, A., Kist, R. and Peters, H.
malocclusion: a systematic review and meta- (2010). Genetic interactions between pax9
analysis. Open Journal of Epidemiology, and msx1 regulate lip development and
2(2012), 75-82. several stages of tooth morphogenesis.
Hartsfield Jr, J. K., Otero, L. M., & Morford, L. A. Developmental Biology, 340(2), 438-449.
(2012). Genetic factors affecting facial Nikopensius, T., Saag, M., Jagomägi, T., Annilo,
growth. INTECH Open Access Publisher, T., Kals, M., Kivistik, P. A., Milani, L. &
125-140. Metspalu, A. (2013). A missense mutation in
Ismail, K., Ghazali@Suhaimi, S. S., Abu Bakar, DUSP6 is associated with Class III
N., Mokhtar, K. I., and Kharuddin, A. F. malocclusion. Journal of Dental
(2017). Demographic characteristics and Research, 92(10), 893-898.
analysis of malocclusions of orthodontic Nishio, C., & Huynh, N. (2016). Skeletal
patients seen at IIUM Dental Specialist malocclusion and genetic expression: an
Clinic, Kuantan, Pahang. International evidence-based review. Journal of Dental
Medical Journal Malaysia, 16(2), 107-111. Sleep Medicine, 3(2), 57-63.
Jang, J. Y., Park, E. K., Ryoo, H. M., Shin, H. I., Nowrin, S. A., Basri, R., Alam, M. K., Jaafar, S.,
Kim, T. H., Jang, J. S., Park, H.S., Choi, J.Y. Mokhtar, K. I. (2019). Class III malocclusion:
& Kwon, T. G. (2010). Polymorphisms in the missense mutations in DUSP6 gene.
matrilin-1 gene and risk of mandibular Pesquisa Brasileira em Odontopediatria e
prognathism in Koreans. Journal of Dental Clínica Integrada. 19:e4709
Research, 89(11), 1203-1207. Peters, H., Neubüser, A., Kratochwil, K., &
Jena, A. K., Duggal, R., Mathur, V. P., & Parkash, Balling, R. (1998). Pax9-deficient mice lack
H. (2005). Class-III malocclusion: genetics or pharyngeal pouch derivatives and teeth and
environment? A twins study. Journal of exhibit craniofacial and limb abnormalities.
Indian Society of Pedodontics and Genes & Development, 12(17), 2735-2747.
Preventive Dentistry, 23(1), 27. Rowlerson, A., Raoul, G., Daniel, Y., Close, J.,
Joshi, N., Hamdan, A. M., Fakhouri, W. D. (2014). Mauragr, C. A., Ferri, J., et al. (2005). Fiber-
Skeletal malocclusion: a developmental type differences in masseter muscle

9
 International Journal of Orofacial and Health Sciences (2020) 1(1)

associated with different facial morphologies. Walther, D.P., Houston, W. J. B., Jones, M. L., et
American Journal of Orthodontics & al. (1994). Walther and Houston’s
Dentofacial Orthopedics, 127, 37-46 Orthodontic notes. Oxford: Wright.
Saad, M. M., Abd Rahman, N. A., Mokhtar, K. I., Weinberger T. (1993) Angle classification.
Abu Bakar, N. (2018). Preliminary study of American Journal Orthodontics and
PAX9 single nucleotide polymorphism Dentofacial Orthopedics. 103 (4), 26A, 28A,
(rs8004560) in patients with class II skeletal 30A.
base malocclusion contributed by mandibular Yahya, S. N., Abdul Razak, N. S., Mokhtar, K. I.,
retrognathism. Archives of Orofacial Sciences. Abu Bakar, N. (2018). A preliminary study on
13 (2): 112-118. MYO1H single nucleotide polymorphism
Salzmann, J. A. (1950) Principles of Orthodontics (rs10850110) in mandibular prognathism in
J. B. Lippincott Company; 2nd edition. Malay Population. Journal of International
Seo, Y. J., Park, J. W., Kim, Y. H., & Baek, S. H. Dental and Medical Research. 11 (2), 607-
(2013). Associations between the risk of 613.
tooth agenesis and single-nucleotide
polymorphisms of MSX1 and PAX9 genes in
nonsyndromic cleft patients. The Angle
Orthodontist, 83(6), 1036-1042.
Soh, J., Sandham, A., and Chan, Y. H. (2005)
occlusal status in Asian Male adults: the
angle orthodontist. International Journal of
Orthodontics and Dentofacial Orthopaedics,
75(5), 814-820.
Sun, R., Wang, Y., Jin, M., Chen, L., Cao, Y.,
Chen, F. Identification and functional studies
of MYO1H for mandibular prognathism.
(2018). Journal of Dental Research. 97 (13),
1501-1509.
Tassopoulou-Fishell, M., Deeley, K., Harvey, E.
M., Sciote, J., & Vieira, A. R. (2012). Genetic
variation in myosin 1H contributes to
mandibular prognathism. American Journal
of Orthodontics and Dentofacial Orthopedics,
141(1), 51-59.
Wall, M. D. (2009). Association analysis of class
II division 2 malocclusion and two genes
linked to hypodontia (MSX1 and PAX9)
(Doctoral Dissertation).

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