Dr.

Abhijeet Kumar Sadhu

Department of orthodontics and
dentofacial orthopedics
New horizon Dental College And Rersearch
Institute, Sakri
 Contents
⚫ Introduction
⚫ Molecular basis for inheritance
⚫ Modes of inheritance
⚫ Population Genetics
⚫ Methods of studying role of genes
⚫ Genetic Mutation
⚫ Homeobox Genes
⚫ Disorders in tooth morphogenesis
⚫ Influence of Genetics in Malocclusion
⚫ Genetic Influence on Tooth Number, Size, Morphology, Position, and Eruption
⚫ Genetic factors in external apical root resorption
⚫ Practical and Clinical Implications
⚫ Conclusion
 Introduction
1. Genetics, (Ancient Greek γενετικός genetikos,
“genitive” and that from γένεσις genesis, “origin”)

2. Genome

3. Gregor Mendel in the mid-nineteenth century.

4. The Human Genome Project (HGP) 1990 – 2003.

U.S. Department of Energy and the National
Institutes of Health
 Molecular basis for inheritance
1. DNA

2. Purines: Adenine (A)

Guanine (G)
Pyramidines: Thymine (T)
Cytosine (C)
Solenoid Model Of Chromosome Structure
 Genes
 Represent the smallest physical and functional unit
of inheritance.

 Alleles
 Homozygous
 Heterozygous
Autosomal Dominant

Dwarfism, Polydactyly and Syndactyly, Hypertension, Hereditary Edema

Autosomal Recessive

Congenital Deafness, Diabetes Mellitus, Sickle Cell anemia, Albinism

X linked Recessive Inheritance

Red-green colour blindness, haemophilia

Multifactorial inheritance.
The trait is determined by the interaction of a number of
genes at different loci, each with a small, but additive
effect, together with environmental factors.
 Discontinuous Multifactorial traits
 Traits determined by multiple gene loci which are
present or absent depending on the number or nature of
the genetic, and/or environmental factors acting.
 Cleft lip and palate is a multifactorial trait.
 Continuous multifactorial traits.
 Many normal human characteristics are determined as
continuous multifactorial traits.
 These traits have a continuously graded distribution.
 For height there is a range from the very tall to the
markedly short
 Malocclusion also is a variation of occlusion in a
continuous multi-factorial trait
Population Genetics
 Population genetics deals with the study of the mode of
inheritance of traits and the distribution of genes in
populations.
Penetrance is a statistical term and indicates the
proportion of individuals carrying a certain gene who
can be detected.
 As our ability to detect the expression of a gene improves,
the penetrance increases.
⚫Expressivity refers to the degree of expression of a
gene in an individual
 Full expressivity for osteogenesis imperfecta would
include fragile bones, dentinogenesis imperfecta, blue
sclerae, and deafness

 The presence of one or two of these findings

comprises Partial expressivity

 The absence of all four, which is occasionally found

in carriers of this gene, is Zero expressivity.
Methods of studying role of genes
 Twin Studies:
The classic way to determine to what extent a
characteristic is determined by inheritance is to
compare monozygotic (identical) with dizygotic
(fraternal) twins.

 Familial studies: Pedigree Studies

Twin Studies
 Monozygotic twins occur because of the early division
of a fertilized egg, so each individual has the same
chromosomal DNA and the two are genetically
identical. (have identical genotypes)
 Any differences between them should be solely the
result of environmental influences

.
⚫Dizygotic twins occur when two eggs are released at
the same time and fertilized by different spermatozoa.
These dizygotic twins are not more similar than
ordinary siblings except that they have shared the
same intrauterine and family environment.

⚫The procedure of study is based on the principle that

observed differences within a pair of monozygotic
twins which will be only due to
influence in dizygotictwins
environmental
due to
and
environment and genotype both
 If condition has no genetic component, e.g. trauma,
concordance rates would be similar for both types of
twins.

 For single gene trait monozygotic concordance will be

100%.whereas dizygotic rate will be less than this and
equal to the rate in siblings.

 For discontinuous multifactorial traits with both

genetic and environmental contributions, the rate in
monozygotic twins, although less than 100%, will
exceed the rate in dizygotic twins.
 In cleft studies, the monozygotic twin concordance
rate for CL(P) and for CP is 35 and 26 per cent,
respectively, and for dizygotic twins 5 and 6 per cent,
respectively (Connor and Ferguson-Smith, 1993)

 Greater the difference between two twin categories

greater is genetic effect in variability of trait, so higher
is heritability of trait.
Familial studies: Pedigree Studies
 Definite trait studied along family tree.

 Based on the recurrence of some easily seen trait in

different generations of the same family. e.g Hapsburg
jaw.
Genetic Mutation
⚫ Gene alleles are usually transmitted unaltered from one
generation to the next, rare events occur that cause changes
within them -these events are called mutations
⚫ If it occurs during gametogenesis the mutant allele will
appear in a gamete and, consequently, in cells throughout
the body of any resulting individual.

⚫ If it occurs after fertilization, as a somatic mutation, only a

proportion of cells will be affected.
Mutations of DNA
⚫ Length mutations - gain or loss of genetic material
⚫ Point mutations - alteration of the genetic code, but no gain
or loss of genetic material.

Chemicals which cause DNA mutations:

1. Base analogues which mimic standard bases, but pair

improperly (e.g. 5-bromouracil);
2. Alkylating agents which add alkyl groups to bases and so
hamper correct pairing (e.g. nitrogen mustard or ethyl
methanesulphonate);
3. Intercalating agents which intercalate with DNA and
distort its structure (e.g. deamination by hydroxylamine).
Homeobox Genes
⚫ Homeobox genes are genes
which are highly conserved
throughout evolution
of diverse organisms and are
known
now play a role
to
patterning in the embryonic
development

Master genes for the development of

Craniofacial complex
 Homeobox genes in craniofacial development :
 Hox group
 Msx1 and Msx2 (muscle segment)
 Dlx (distalless)
 Otx (orthodontical)
 Gsc (goosecoid), and
 Shh (sonic hedgehog).
 Vehicles through which homeobox gene information
is expressed in the co-ordination of cell migration and
subsequent cell interactions that regulate growth
(Johnston and Bronsky, 1995).

 Fibroblast growth factor (FGF),

 Epidermal growth factor (EGF),
 Transforming growth factor alpha (TGF ),
 Transforming growth factor beta (TGF ),
 Bone morphogenetic proteins (BMPs)
Control of tooth development.
⚫ Homeobox genes have particular implications in
tooth development and, therefore, on Orthodontics.

⚫ Muscle specific homeobox genes

⚫Msx-1 and Msx-2 appear to be involved in epithelial
mesenchymal interactions, and are implicated in
craniofacial development, and in particular in the
initiation of developmental position (Msx-1) and
further development of the tooth buds (Msx-2)
(MacKenzie et al., 1991; Jowett et al., 1993)
 Further evidence of the role of Msx1 comes from gene
knock-out experiments which results in disruption of
tooth morphogenesis among other defects (Satokata
and Maas, 1994).

 Pax9 is also transcription factor necessary for tooth

morphogenesis (Neubuser et al.,1997).
 Bone morphogenetic proteins (BMPs) are members of
the transforming growth factor family (TGF ) and they
function in many aspects of craniofacial development
with tissue specific functions.

 BMPs have been found to have multiple roles not only

in bone morphogenesis, (BMP 5 for example induces
endochondral osteogenesis in vivo), but BMP 7
appears to induce dentinogenesis (Thesleff, 1995).
Disorders in tooth morphogenesis.

⚫ Amelogenesis imperfecta (AI): Group of

heterogeneous genetically
disorders affecting enamel formation.
Heterogeneous, hypoplastic, hypocalcified
and
hypomaturation
In humans, two amelogenin AMGX and AMGY have been
cloned and mapped to the X and Y chromosomes, respectively
 Dentinogenesis imperfecta (DI): Brownish
discolouration of the teeth, crowns susceptible to
rapid attrition, fragile roots and pulp chamber
obliteration due to abnormal production of dentine
matrix (Shields, 1973).

 Mutations of DSPP gene in locus 4q21 substitutions in

genes with encode for sub-units of type 1 collagen
(Ganguly et al., 1991; Nicholls et al., 1996).
⚫ Hypodontia: muscle specific homeobox gene (MSX1) ON 4p
is strongly expressed in the dental mesenchyme throughout
the bud, cap and bell stages of odontogenesis

⚫ Satokata and Maas (1994) found that mice with the Msx1
gene knocked out had amongst other defects, complete
failure of tooth development at the bud stage.
 Ectodermal dysplasia (EDA): Heterogeneous disorder
with many clinically distinct types, and is characterized
by the triad of hypotrichosis (sparse hair),
hypohydrosis (lack of sweat glands), and hypodontia
(reduced number of teeth).

 Kere and his colleagues (1996) identified the EDA gene

X linked recessive.
Influence of Genetics in Malocclusion
The Nature of Malocclusion
 Malocclusion may be defined as a significant deviation from
what is defined as normal or ‘ideal’ occlusion (Andrews,
1972).
 Population groups that are genetically homogeneous tend to
have normal occlusion.
 In pure racial stocks, such as the Melanesians of the
Philippine islands, malocclusion is almost non-existent.
 In heterogeneous populations, the incidence of jaw
discrepancies and occlusal disharmonies is significantly
greater
⚫Corruccini RS. An epidemiologic transition in dental
occlusion in world populations. Am J Orthod.
1984;86:419–426..
⚫ Chung CS, Niswander JD, Runck DW, Bilben SE,
Kau MC. Genetic and epidemiologic studies of oral
characteristics in Hawaii’s schoolchildren. II.
Malocclusion. Am J Hum Genet. 1971;23:471–495
Family Studies of Heritability of Dentofacial Types

Class II Division 1 Malocclusion

⚫ Harris, 1963,1975: mandible is significantly more retruded than
in Class I patients, with the body of the mandible smaller and
overall mandibular length reduced

⚫ showed a higher correlation between the patient and his

immediate family than data from random pairings of unrelated
siblings, thus supporting the concept of polygenic inheritance for
Class II division 1 malocclusions.
Class II Division 2 Malocclusion

⚫Familial occurrence of Class II division 2 has been

documented in several published reports including twin
and triplet studies (e.g. Kloeppel, 1953; Markovic,
1992) and in family pedigrees from Korkhaus
(1930).
 Studies point to autosomal dominant with
incomplete penetrance and variable expressivity.
 Class III Malocclusion
⚫ Most famous example of a genetic trait in humans passing
through several generations is the pedigree of the Hapsburg
jaw.
⚫ Strohmayer (1937) concluded from his detailed pedigree
analysis of the Hapsburg family line that the mandibular
prognathism was transmitted as an autosomal dominant trait
with incomplete penetrance.

⚫ Suzuki 1961 studied 1362 persons in 243 Japanese families

which had mandibular prognathism and showed higher
incidence of trait in the members of family(34.3%) than
families of individuals with normal occlusion (7.5%).
Genetic Influence on Tooth Number, Size,
Morphology, Position, and Eruption

⚫ Twin studies have shown that tooth crown dimensions are

strongly determined by heredity (Osborne et al., 1958).

⚫ Molecular genetics of tooth morphogenesis with the Hox7

and Hox8 (now referred to as MSX1 and MSX2) genes
being responsible for stability in dental patterning
(Mackenzie et al., 1992)
Abnormal shape

 Alvesalo and Portin 1969 supported that malformed and

missing lateral incisors maybe result of common gene defect.

 Peg lateral , microdontia ,missing teeth all have familial trends,

female preponderance, association with other dental anomalies.

 So polygenic aetiology is suggested.

 Ectopic maxillary canines
Peck et al in 1994 concluded that palatally ectopic
canines were inherited trait along other anomalies.

 Mossey et al in 1994 showed association between

ectopic canine and classII div 2 malocclusion.
Hypodontia
 Maybe part of syndrome e.g ectodermal dysplasia.

 Msx1 and Pax9 genes involved in non

autosomal
syndromic dominant hypodontia.

 Missing maxillary lateral incisor – polygenic model

maybe autosomal dominant with incomplete
penetrance and variable expressivity.

 Markovic 1982 found high rate of concordance for

hypodontia in monozygotic twins.
 Submerged primary molar

 In monozygotic twins there is high concordance rate

providing evidence for genetically determined failure of
eruption (Helpin and Duncan 1986)

 Variety of anomalies are associated with tooth

submergence.

 Taurodontism may form a part of this syndrome(Winter et

al 1997)
Genetic factors in external apical root
resorption
 External apical root resorption (EARR) is a common
clinical complication of orthodontic treatment.

 The analysis of 35 families indicated that the IL-1B

polymorphism accounts for 15% of the total variation
seen for EARR seen in the maxillary central incisor in
the sample studied.
Practical and Clinical Implications
 Skeletal jaw and malocclusion of
discrepancies geneticcan be successfully treated
origin
orthodontically, except in extreme cases
surgical intervention is required. where

 It is possible to modify the direction of dentofacial

growth using orthodontic appliances and therefore
change or forestall morphogenetic abnormalities
(Graber, 1969; Harvold et al., 1981; Moss and
Salentijn, 1997)
 Orthodontic correction of a malocclusion is in
effect altering the phenotypic of a
expression particular morphogenetic pattern.

 The degree to which this can be successfully achieved

depends on
 (a) the relative contribution of each factor
to the existing problem, and
 (b) the extent to which skeletal pattern
can be influenced by orthodontic and orthopaedic
appliances.
Diagnostic goal
 To determine the relative contribution of genetics and the
environment.

 The greater the genetic the worse the

prognosis for a successful outcome by
component, means
orthodontic intervention. of
Conclusion
 Multiple factors and processes contribute to the
response to orthodontic treatment. Some patients will
exhibit unusual outcomes linked to polymorphic genes.
 The influence of genetic factors on treatment outcome
must be studied and understood in quantitative terms.
 Conclusions from retrospective studies must be
evaluated by prospective testing to truly evaluate their
value in practice.
References
⚫ The Heritability of Malocclusion: Part 1—Genetics, Principles and
Terminology. P. A. M O S S E Y, British Journal of Orthodontics/
Vol. 26/1999/103–113
⚫ The Heritability of Malocclusion: Part 2- Influence of Genetics in
Malocclusion. P. A. M O S S E Y, British Journal of Orthodontics/
Vol. 26/1999/195–203
⚫ Personalized Orthodontics, The Future of Genetics in Practice, James
K. Hartsfield, Jr., Seminars in Orthodontics, Vol 14, No 2 (June), 2008: pp
166-171
⚫ Genetic Factors and Orofacial Clefting Andrew C. Lidral, Lina M.
Moreno, and Steven A. Bullard, Seminars in Orthodontics, Vol 14, No 2
(June), 2008: pp 103-114
⚫ Investigation of Genetic Factors Affecting Complex Traits Using
External Apical Root Resorption as a Model Shaza K. Abass and
James
K. Hartsfield, Jr. Seminars in Orthodontics, Vol 14, No 2 (June), 2008: pp
115-124
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