GOOD MORNING

GENETICS IN ORTHODONTICS

PRESENTED BY:
DR M GREESHMA HARINI
1ST YEAR POST GRADUATE
DEPARTMENT OF ORTHODONTICS
AND DENTOFACIAL ORTHOPAEDICS
NARAYANA DENTAL COLLEGE
 CONTENTS
 Introduction
 History
 Basic Terminologies
 Transcription And Translation
 Modes Of Inheritance and transmission
 Types Of Studies Involved In Genetics
 Genetics And Craniofacial Growth
 Role Of Homeobox Genes
 Mode Of Transmission Of Inherited Structures
 Genetic Influence On Dentition
Influence On Bilateral Symmetry
Cleft Lip And Palate
Root resorption
Pain perception and temporomandibular dysfunction
Effect of hereditary on soft tissues
Applications Of Genetics
• Genetic screening
• Postnatal diagnosis
• Genetic counselling
• Gene therapy
Conclusion
References
 INTRODUCTION

 Growth is the combined result of interaction between

several genetic and environmental factors overtime.

 Malocclusion is a manifestation of genetic & environmental

interaction on the development of the oro-facial region.

 Consideration of genetic factors is an essential element of

diagnosis that underlies virtually all dentofacial anomalies .

 This part of the diagnostic process is important to

understand the cause of the problem before attempting
treatment .
 Because if the problem is genetic , then orthodontists may be
limited in what they can do or change
 HISTORY
• Genetics is derived from the Ancient Greek word ‘GENETIKOS’.
Scientist year Contribution

Bateson 1906 Greek root gen, meaning “to

become” or “to grow into”.
Gregor John Mendel 1822-1884 Father of modern genetics.
Law of segregation

Sulton and Boveri 1903 Chromosomal Theory of

Inheritance.
Thomas Hunt Morgan studied the arrangement of
genes along chromosomes.
Watson and Crick 1953 the structure of DNA molecule.

Finch and Klung. Solenoid model of chromosome

 BRIEF HISTORY OF GENETICS
Aristotle and Hippocrates, in the 4th century BC, are generally
credited with the first scholarly efforts to provide an explanation of
the mechanisms of heredity.
 Pre-Mendelian Era (19th Century)
 Classical Era (1900-1930)
 DNA Era (1930-1970)
 Genomics Era (1970-2010)
 Postgenomic/Epigenomic Era (2010-
 Precision medicine period.

David S. Carlson, Evolving concepts of heredity and genetics in orthodontics by the American Association of
Orthodontists. (Am J Orthod Dentofacial Orthop 2015;148:922-38)
 BASIC TERMINOLOGIES
• Webster’s definition:
Genetics “the branch of biology which deals with heredity and variations
among related organisms, largely in their evolutionary aspect.”
Heredity is the transmission of genetic or physical traits from parent to
offspring.
Variation: “the tendency through which the organism differ in specific ways
from one another.”
Genome – The entire genetic content of a set of chromosomes present
within a cell or an organism.
Genes – Represent the smallest physical and functional units of
inheritance that reside in specific sites called loci in the genome .
A gene can be defined as the entire DNA sequence necessary for the
synthesis of a functional polypeptide or RNA molecule .
Alleles –. Gene at the same locus on a pair of homologous chromosomes
Or genes responsible for contrasting characters
Or, the alternative forms of a particular gene.
Trait – Particular aspect or characteristic of the phenotype Can be,
monogenic , polygenic and multifactorial .
Genotype - Genetic composition of trait ex. AA, Aa, aa.
Phenotype - Outward appearance of a trait Ex. haircolor, height.
Dominant – An allele that express its phenotype when heterozygous with
recessive allele.
Eg- A is dominant over a . AA, Aa.
Recessive – An allele that does not express its phenotype when
heterozygous with dominant allele.
i.e. a is recessive to A. or recessive genes can only express themselves
in the absence of the dominant gene (aa).

The Heritability of Malocclusion: Part 1—Genetics, Principles and Terminology(P. A. MOSSE Y, B.D.S., P H.D., D.O R T H.,
M.O R T H., F.D.S., F.F.D.)
Chromosomes are thread like darkly
staining bodies within the nucleus,
composed of DNA and chromatin which
carry the genetic information.
Composition:
DNA, Histones + acid proteins
Interaction between these chromosomes
that lead to the phenomenon of inheritance.
 Human Cell
46 chromosomes
(23 pairs)

Autosomes Sex chromosomes

22 Pairs 1 Pair

( Female - XX
Male - XY)
 TRANSCRIPTION AND TRANSLATION

DNA:
• First described by James Watson & Francis Crick

• Right – Handed Double helix, present in the chromosome &

contains the genetic information.

• Composed of a sugar phosphate backbone & attached bases –

connected to strand by hydrogen bonding

• Chemical bases – 4 in number

• Adenine (A) , Guanine (G) , Thymine (T) , Cytosine (C)
 MITOSIS

• is the process by which a cell, which has

previously replicated each of its chromosomes.
• Autosomal chromosomes are replicated through
mitosis.
• Cells reproduce by dividing into two identical
cells
 MEIOSIS

• A special type of cell division

• Used to make sex cells
• Meiosis halves the numbers of chromosomes
• Meiosis picks one chromosome from each pair at random
and places them in a sex cell. This results in enormous
variation amongst the sex cells.
CHROMOSOMAL ABBERATIONS

• Definition: Alterations of the genetic material which

involves many genes and large amounts of DNA are
considered together as the chromosomal abberations.

• Classification
Numerical abberation
Structural abberation
Mosaicism
1. Numerical abberations
• Euploidy –triploidy, tetraploidy
• Aneuploidy –monosomies, trisomies

2. Structural aberrations
• Translocations –transfer of genetic material from one
chromosome to another.
• Inversions-rearrangement within the same chromosome
segment and is rotated 180 degrees.
• Insertion –one segment is removed from normal position &
inserted in different position.
• Deletion– a missing chromosomal segment.
• Ring chromosome.
• Isochromosome.
3. Mosaicism- The presence of two or more types of
populations of cells in the same individual.
• In the context of chromosome numbers, postzygotic mitotic
nondisjunction would result in the production of a trisomic
and monosomic daughter cell and the descendants of these
cells would then produce a mosaic.
 Gene mutations are known as a change induced by certain
agents in the composition of base pairs of DNA which results in
altered protein synthesis and altered expression of certain
traits.
 Mutagens are ionizing radiation, chemicals, certain viruses, and
high temperature.
 On the basis of genes involved, these may be point mutations or
chromosomal mutations which are inherited or transmitted by
different modes of inheritance as monogenic, polygenic, and
multifactorial.
 In monogenic pattern traits develop due to the influence of a
single gene. This monogenic inheritance will occur by autosomal
dominant, recessive, and X-linked recessive transmission.
 WHY SHOULD A STUDENT OF ORTHODONTICS
BE INTERESTED IN GENETICS?

• To know exactly why or how malocclusion occurs.

• To what extent does it express in the next generation.
• To know prevalence
• To know its reaction to treatment plan.
• To segregate inherited malocclusions from environment
malocclusions
 MENDEL’S LAWS
• LAW OF DOMINANCE: a unit of genetic information
is transmissible unchanged from generation to generation.
• Third law or Law of Independent assortment –

• When 2 characters are combined in a hybrid, segregation of one

pair of characters is independent of other pair of characters.
• Law of Uniformity –when two homozygotes with different
alleles are crossed, all of the off springs of first generation are
identical heterozygotes.
• Law of Seggregation –each individual possess two factors
which determine specific characteristic, a parent transmits only
one of these factors to any particular offspring. It is purely a
matter of chance which of the two factors get transmitted to
which offspring.
 MODES OF INHERITANCE
• Genetic disorders can be mainly classified as
1. Mendelian disorders (Single gene)
1. Autosomal dominant (AD)
2. Autosomal recessive (AR)
3. X-linked recessive (XLR)
4. X-linked Dominant (XLD)
2. Chromosomal disorders
1. Numerical abnormalities
2. Structural abnormalities
3. Multifactorial disorders/ Polygenic 32
Autosomal dominant
(one allele is sufficient for expression of trait)

- Trait occurs in generations

- 50% of offsprings will have the trait
- Male and female have equal predilection.
- parents who do not have the trait have offspring who do not
have the trait
Autosomal recessive

- Trait occurs in generations

- Here 2 copies of an abnormal gene must be present in
order for the disease or trait to develop.
- 25% of offsprings will have the trait
 X linked Recessive :
• Genetic trait or condition can be passed down from parent to
child through mutations (changes) in a gene on the X
chromosome.
• In males (who only have one x chromosome), a mutation in the
copy of the gene on the single x chromosome causes the
condition.
• Females (who have two x chromosomes) must have a mutation
on both x chromosomes in order to be affected with the
condition.
• If only the father or the mother has the mutated x-linked gene, the
daughters are usually not affected and are called carriers because
one of their x chromosomes has the mutation but the other one is
normal.
• Sons will be affected if they inherit the mutated x-linked gene
from their mother. Fathers cannot pass x-linked recessive
conditions to their sons.
 X-linked dominant inheritance:
• Genetic trait or condition can be passed down from parent to
child through mutations (changes) in a gene on a single X
chromosome.
• In females (who have two x chromosomes), a mutation in a
gene on one of the x chromosomes is enough to cause the
condition. In males (who only have one X chromosome), a
mutation in the copy of the gene on the single X chromosome
causes the condition.
• Fathers cannot pass x-linked dominant conditions to their
sons, but all daughters of affected fathers will be affected with
the condition and can pass it on to their children.
MULTIFACTORIAL INHERITANCE:

 If the genetic variation of a particular phenotypic trait is dependent

on the simultaneous segregation of many genes and affected by
environment.

E.g. Congenital heart defects, neural tube defects, cleft lip and palate .
 
POLYGENIC VARIATION:

 Involves the inheritance and expression of a phenotype being

determined by many genes at different loci, with each gene
exerting a small additive effect.
 Additive implies that the effects of the genes are cumulative, i.e. no
one gene is dominant or recessive to another.

E.g. Height , skin color

 MODES OF TRANSMISSION OF
MALOCCLUSION
• 3 types:

1. Repetitive Traits
2. Discontinuous Traits
3. Variable Traits
 THEORIES

1. Genetic theory
2. Moss’s Revisitation of FMH
3. Butler’s Field theory
 GENETIC THEORY

Allan Brodie (1941)

Genes

Determine the overall control

of craniofacial growth
 MOSS’S REVISITATION OF FMH

Resolving the roles of genomic and epigenetic processes

That control growth and development

Genetic factor – Intrinsic (primary cause)

Epigenetic – extrinsic (proximate)
 BUTLER’S FIELD THEORY

States that mammalian dentition can be divided into several

developmental fields

Molar/premolar, the canine & the incisor fields

Within each developmental field, there is a key tooth, which is

more stable developmentally and on either side of this key
tooth, the remaining teeth within the field become
progressively less stable.
TWIN STUDIES:

Are the studies carried out in twins.

Pioneer – Sir Francis Galton (1822-1911).
He argued that HEREDITY (NATURE) plays a stronger role than
ENVIRONMENT ( NURTURE) in determining characteristics of
TWINS.
• There are two different types of twins
- Monozygotic (MZ)
- Dizygotic (DZ)

- (MZ: developing from a single fertilized egg and therefore

sharing all of their genes)—or dizygotic (DZ: developing from
two fertilized eggs and therefore, sharing on an average 50
percent of their genes, the same level of genetic similarity as
found in non-twin siblings)

• Monozygotic twins have identical genotype, whereas

dizygotic twins are only as alike as siblings.
• Monozygotic twins are concordant.  
• For a single gene trait or a chromosomal disorder, the
monozygotic concordance rate will be 100%, whereas the
dizygotic rate will be less than this.
CONCORDANCE & DISCORDANCE
• Twins are concordant if both the monozygotic twins show
a discontinuous trait and discordant if only one shows the
trait.

• As twins usually share a similar family environment it

may be difficult to separate the relative extent of
environmental (nurture) and genetic contributions (nature)
to a multifactorial trait
• Monozygotic twins have similar genotypes
• Dizygotic twins are like siblings.
• If a condition has no genetic component concordance would be
expected to be similar for both types of twins.

• For a single-gene trait or a chromosomal disorder the

monozygotic concordance rate will be 100%, whereas the
dizygotic rate will be less than this and equal to the rate in
siblings.
Zygosity determinants:

• Comparisons of physical features

• Examination of blood groups & enzyme

polymorphisms

• Obtaining blood samples to extract DNA

• Isolating DNA from cheek cells obtained using buccal

swabs
 Twin study designs:

4 designs-

 1. The MZ co-twin design

 2. Twins reared apart

 3. Opposite sexed DZ twin

 4. The twin half sib model

1. The MZ co-twin design

• studying MZ twin pairs who show different phenotypic

expressions for a particular trait or disease under
investigation.
• Alternatively, researchers can manipulate the environment
so that each member of a twin pair is exposed to different
environmental conditions.

• An approach using this model that has been reported in the

orthodontic literature, is the provision of different treatments to
the two members of an MZ twin pair and observation of the
outcomes.
 
- Martin et al. have pointed out, it is often assumed that these
environmental factors are exogenous to the individual, e.g., related
to lifestyle, but a variety of endogenous events leading to
alterations in cellular development and differentiation,

- e.g., from differences in the timing or degree of methylation of

autosomal genes, may also lead to differences in phenotypic
expression between MZ twin pairs.

- Eg. variation in expression of

- missing,
- peg-shaped,
- diminutive and normally-formed upper lateral incisors within pairs
of MZ twins.
2.Twins reared apart

Studies of MZ twin pairs reared apart have confirmed the important

role played by genes in both dental morphology and caries experience.
(Boraas et al 1988).
3. Opposite sexed DZ twin

• Comparison of correlations between same-sex DZ pairs and

opposite-sexed (OS) DZ pairs provide an opportunity to
investigate whether primary or secondary sexual
characteristics are affected by diffusion of hormones in utero.
• We all know that diffusion of hormones may occur in humans via
the maternal circulation
• There is also evidence that testosterone can diffuse across the
amniotic membranes separating rat fetuses
• Eg. Comparisons of dental crown diameters in females from
same-sex DZ pairs with females from (OS) DZ pairs has revealed
that the latter have larger teeth, on average. Diffusion of sex
hormones from male to female co-twins in utero may account for
the increased tooth size in OS females.
4. The twin half sib model
Involves making comparisons between the offspring of
MZ pairs and their partners. The advantage of this
model is that the children of MZ pairs who are born to
different mothers are themselves genetically half-
siblings.
GENES AND CRANIOFACIAL GROWTH

• It is genetically accepted that the basic form of a part of

the neurocranium and splanchnocranium is determined
genetically in the cartilaginous precursor during
embryonic development.  
• Basic form of the mandibular body and the location and
morphology of the nasal capsule (which gives rise to the
pyriform aperture) are genetically determined in the
chondrocranium.
• The form and size of the teeth are also principally
genetically determined.
• The genetic control is also located in the neurological,
muscular and neuromuscular fields, which have an indirect
influence on the skeleton.
Genes Function
OTX2, Lim1 and HESX1 genes the anteroposterior axis of
embryonic disc
TGF-beta. Primitive streak is initiated and
maintained by
BMP-4 ventralisation of mesoderm

Chordin, noggin and follistatin dorsalize the cranial mesoderm

to form notochord , somites and
somitomeres
Goosecoid inhibition of BMP-4 leading to
neural induction.
Transforming growth factors – important role in tissue
beta 1 , 2 and 3 regeneration, cell proliferation
and embryonic development.

Fibroblast growth factors 1,2 and 3 important role in tissue

regeneration, cell proliferation
and embryonic development.
 Mutations in FGFs are associated with some
craniofacial syndromes like

• CROUZON,
• APERT,
• PFEIFFER,
• BEARE STEVENSON,
• JACKSON – WEISS etc.
 CHROMOSOME ABNORMALITY
• 13 trisomy---Patau’s Syndrome
Mental retardation
Microcephaly
Cleft lip/palate
Micrognathia,small eyes

• 18 trisomy--- Edward’s Syndrome

Mental retardation
Brachycephaly
Micrognathia
Hypodontia
CLP
• XO ---Turner’s Syndrome
Retarded growth
Micrognathia
Spade like chest
Ovarian agenesis

• 21 trisomy --Down’s Syndrome.

Brachycephaly
Mental retardation
Max hypoplasia
Flat nasal bridge
Delayed eruption
Growth retardation
Macroglossia
 ROLE OF HOMEOBOX GENES
• Large family
• directs the formation of many body structures during early
embryonic development.
• In humans : Homeobox gene family contains
 235 functional genes
 65 pseudogenes.
• Homeobox genes often appear in clusters.
 Activities:
• Formation of Limbs and organs along the axis (from head to
tail).
• Regulates the process by which cells mature to carryout specific
function.
• Discovered by Edward Lewis
• In the FRUIT FLY
• During evolution from Drosophila – fruit fly transferred to
vertebrates.
• 1st cloned in frog(McGinnis et al;1984) and followed by
mouse (Carrasco et al;1984)
 TRUNK
’3’ HIND BRAIN ’5’
• These are regarded as master genes of head and neck which
control:
 - Patterning
 - Induction
 - Programmed cell death and
 - Epithelial mesenchymal interaction , during the development of
craniofacial complex.
Genes that encode for proteins called TRANSCRIPTION
FACTORS.
The vehicles through which HOMEOBOX genes express their
information include :
• FGF,
• EGF,
• TGF-alpha and beta,
• BMPs.
HOX genes control the patterning of pharyngeal arches (except 1 st
arch).
PATTERNING OF FACE AND JAWS (HOX)

 MSX (muscle segment genes ) in mammals.

• - MSX 1 defect causes clefting, deficiency in alveolar

bone, aberration in tooth development and missing teeth.

• - MSX 2 defect cause multiple inductive failures and early

death.

• - combined defect of MSX 1 and 2 cause deficiency in

calvarium, teeth and alveolar bone.

 SHH and FGFR expressed in early palatal epithelium.

Their disruption causes failure of growth of palatal processes.
• DLX (distal less genes) are involved in neural crest derived
skeletal elements of 1st and 2nd branchial arches.

• Goosecoid (GSC) is involved in organization of complete

body axis of embryo and is also essential for inductive
interactions during formation of head.

• SHH (sonic hedge hog genes) are involved in left-right

asymmetry, determination of polarity in CNS, somites and
limbs and in organisation and formation of skeleton.

• Loss of SHH causes defective patterning of neural

plate(holoprosencephaly), failure of cleavage in midline of
brain and cyclopia
• Various odontogenic HOX genes are:
• PAX GENE (paired box homeotic genes)- mutations cause
hypodontia and transposition.
• BARX GENE (bar class homeobox genes)- localized around
developing molars(DLX-2).
• MSX GENE (muscle segment homeobox genes)- expressed in
migrating neural crest cells and in mesenchymal cells of dental
papilla and dental follicle
• DLX GENES- restricted to areas of future molar teeth.
• SHH GENES- is essential for initiation of tooth development,
epithelial signalling and cuspal morphogenesis.
MODE OF TRANSMISSION OF INHERITED STRUCTURES
 
Horowitz et al (1960) studies fraternal and identical adult twin pairs using only linear
cephalometric variables and demonstrated highly significant hereditary variations
in the anterior cranial base, mandibular body length, lower face height and total
face height.
 
Hunter (1965) also used linear measurements on lateral cephalograms and concluded
that there is a stronger genetic component of variability for vertical
measurements rather than for measurements in the anteroposterior dimension.
 
Furnex et al (1967) found boys to show more similarity to their parents than
girls. Facial skeletal structures were more frequently transmitted from mothers to
sons than from mothers to daughters. Female twins showed greater concordance in
facial features than male twins.

Hunter et al (1970) found gentic correlation to be strongest between fathers and

children, especially in mandibular dimensions. There was a significant relation in
facial height between mothers and their offspring.  
 GENETICS AND MALOCCLUSION:
• Stockard (1941) carried out breeding experiements with dogs, and
produced gross orofacial deformities and associated malocclusions.
• He concluded that individual features of the craniofacial
complex could be inherited according to Mendelian principles
independently of other portions of the skull and that jaw size
and teeth size could be inherited independently and as
genetically dominant traits.

• Litten et.al (1970) concluded that siblings usually show similar

types of malocclusion and examination of older siblings can
provide a due to the need for interception and early treatment of
malocclusion.
 
 
GENETIC BASIS OF VARIOUS TYPES OF
MALOCCLUSIONS:

CLASS II DIV. 1

Harris (1963, 1975) in Class II patient, the mandible is smaller

and overall mandibular length reduced.

They found that a higher correlation between the patient and

his immediate family than data from random pairing of
unrelated siblings thus supporting the concept of polygenic
inheritance for Class II Div 1 malocclusion
CLASS II DIV 2 MALOCCLUSION
• Class II division 2 malocclusion comprises the unique combination
of deep overbite, retroclined incisors, Class II skeletal
discrepancy, high lip line with strap like activity of the lower
lip and active mentalis muscle.

• Markovic 1992 carried out a clinical and cephalometric study of

114 Class II Division 2 malocclusion, 48 twin pairs and six sets
of triplets. Intra-and inter pair comparison were made to
determine concordance/discordance rates for monozygotic and
dizygotic twins.
• Of the monozygotic twin pairs, 100% demonstrated
concordance for the Class II division 2 malocclusion, while
almost 90% of the dizygotic twin pairs were discordant. This is
strong evidence for genetics as the main aetiological factor in the
development of Class II Div 2 malocclusion.
CLASS III

• Strohmayer (1937) concluded from his detailed pedigree analysis of

the Hapsburg family line that the mandibular prognathism was
transmitted as an autosomal dominant trait.

• Suzuki (1961) studies Japanese families and noted that while index
cases had mandibular prognathism, there was a significantly
higher incidence of this trait in other family members in
comparison to families of individuals with normal occlusion.
• Schulze and Weise (1965) studies mandibular prognathism in
monozygotic and dizygotic twins and reported a 6 times higher
concordance rate in monozygotic twins than dizygotic twins.

• Both these studies support a polygenic hypothesis as the primary

cause for mandibular prognathism. 
Maxillary Midline diastema:

• Maxillary midline diastema is also found to be of genetic in

origin.

• Gass et al studied the genetic basis of midline diastema in 15

black, 14 white and 1 mixed race.

• This suggest a possible genetic basis for maxillary midline

diastema and a greater role of environmental factors in the black
sample than in the white sample.

• It was found to be autosomal dominant mode of inheritance.

 
 Occlusion and arch width

• Harris and Smith in 1980 studied on the occlusion and arch

width of 1200 samples from 14 villages.
• On average, only about 10 percent of the variation in
overjet, overbite, crowding, tooth rotations, and molar
relationships results from non-environmental causes.
• In contrast, about 60 percent of the variation in
measurements of arch size and shape is attributable to
heredity.
 
 Vertical malocclusion
Vertical malocclusion like deep bite and open bite of skeletal
origin are of heredity in origin.
GENETIC INFLUENCE ON TEETH MORPHOLOGY

 
• Two common morphologic traits are the Cusp of Carabelli and
shovel-shaped incisors - polygenic origin with a discontinuous
varitions.

• Asian populations show the greatest expression of shoveling.

• Cusp of Carabelli - more common in Caucasian groups.
  .
Abnormal tooth shape –

Missing and malformed lateral incisors might be the result of a

common gene defect.
Abnormalities in the lateral incisor region range from peg shaped
to microdont to missing teeth, all of which have familial trends,
female preponderance and association with other dental
anomalies, such as other missing teeth, ectopic canines and
transpositions, suggesting a polygenic etiology.

Alvesalo and Portin (1969)

GENETIC INFLUENCE ON TOOTH NUMBER

• Grahnen 1956 ;If either parent had one or more congenitally missing
teeth, there was an increased likelihood that their children also would be
affected.

• Niswander and Sugaker(1963)  ;Supernumerary teeth most frequently

seen is a pre maxillary conical midline tooth (mesiodens) with a male
sex prediction and appears to be genetically determined.

 
• Mackovic (1982) found a high rate of concordance for hypodontia in
monozygotic twins while dizygous twins were discordant. So, the mode
of transmission could be explained by a single autosomal dominant
gene with incomplete penetrance.
 
• Vastardis (1996) Mutation in MSX gene, located on chromsome 4p,
caused familial tooth agenesis.
Solitary median maxillary central incisor syndrome -
Mutation in the sonic hedgehog (SHH) gene
GENETIC INFLUENCE ON TOOTH SIZE

• Twin studies by Osborne et al (1958) have shown that tooth crown

dimensions are strongly determined by heredity.

• ( Richardson 1975). Studies have shown that the size of permanent

dentition is larger in Negros than Caucasians.

• (Shrestha R, 2005)Mean tooth width in the Nepalese populations was

smaller than in the White Northern European and North American
Caucasian

• Hypodontia and hypoplasia of maxillary lateral incisors are frequently

present simultaneously. Spence (1974) showed that hypodontia and
reduction in tooth size are in fact controlled by the same or related gene
loci and fit the polygenic multifactorial threshold model of inhertance.
 
 GENETIC INFLUENCE ON TOOTH POSITION

• Ectopic maxillary canines –

Peck et al (1994) have concluded that palatally ectopic canines are an
inherited trait being one of the anomalies in a complex of genetically
related dental disturbances, often occurring in combination with
missing teeth, tooth size reduction, supernumerary teeth and other
ectopically positioned teeth.

• Submerged primary molars –

Primary molar submergence occurs most often in the mandibular
arch with a prevalence of less than 10%. The siblings of affected
children are more likely to be affected and in monozygotic twins
there is a high rate of concordance, indicating a significant genetic
component in the etiology 
 
 
GENETICS BASIS OF DISORDER OF TOOTH MORPHOGENESIS
 
Amelogenesis imperfecta (AI)
• Clinically (hypoplastic, hypocalcified and hypomaturation )and genetically
(autosomal dominant, autosomal recessive and X-linked inheritance)
heterogenous disorders affecting enamel formation.
• In humans, two amelogenes, AMGX and AMGY have been cloned and mapped
to the X and Y chromosome respectively.

Dentinogenesis imperfecta (DI)

• autosomal dominant disorder which presents with brownish discoloration of
the teeth, crowns susceptible to rapid attrition, fragile roots and pulp chamber
obliteration.
• The structural defects in collagen type I molecules affects the extracellular
matrix formation, resulting in the pathogenesis of DI.
 
Ectodermal dysplasia (EDA)
• Characterized by the triad of hypotrichosis, hypohydrosis and hypodontia.
• Gene responsible for X-linked EDA was found to be expressed in
Keratinocyetes, hair follicles, sweat glands and in other adult and fetal tissues.
(Kere et al 1996)
 Environmental and Genetic influences on bilateral
symmetry:
Van Valen described three types of asymmetry:

Directional Anti-symmetry Fluctuating asymmetry

asymmetry
Occurs when one side Difference occurs between
Development of is larger than the other right and left sides – inability
one side is different but which side is of individual to develop
from that of other larger cannot be identical, bilaterally.
side during normal predicted before Eg. Primary and permanent
development. development and dentitions, craniofacies.
Eg. Lobes of right varies in normal
and left lungs development.

It indicates how well a

genome can produce an ideal
Both are genetically determined phenotype under certain
circumstances.
GENETIC BASIS OF CLEFT LIP AND PALATE
Orofacial clefts-
• Cleft lip with or without cleft palate (CL/P)
• Cleft palate only (CPO)
 
• Nonsyndromic (isolated)
• Syndromic

Approximately 30% of CL/P and

50% of CPO, are syndromic.

• Both genetic and environmental factors playing an important and

influential role (Murray, 2002).

• (Mitchell and Risch, 1992; Gortin et.al, 2001). The sibling risk for
CLP is approximately 20 times higher than that for the normal
population, while the concordance rate in monozygotic twins is
approximately 25-45% as opposed at 3-6% for dizygotic twins
 ROOT RESORPTION

• Heritability estimates have shown that approximately half of EARR

variation concurrent with orthodontia, and almost two-thirds of maxillary
central incisor EARR specifically, can be attributed to genetic variation.
• Harris et al in his study stated that Although external apical root
resorption (EARR) is affected by severity of malocclusion, these effects
are independent of a direct genetic control over the person's susceptibility
to EARR.
• Moderately high heritability for EARR occurs because there is
significantly more variation among families than among siblings within
families. Clinically, this means that siblings experience similar levels of
EARR in response to orthodontic treatment.

Edward F. Harris.A heritable component for external apical root resorption in patients treated orthodontically; Am
J Orthod Dentofac Orthop 1997;111:301-9.
 PAIN PERCEPTION AND
TEMPOROMANDIBULAR DYSFUNCTION
• Although the individual etiologies of TMJ disorders are heterogeneous and
probably often complex.
• Genetic factors may play a role in TMD by influencing variation in individual
pain perception, production of proinflammatory cytokines, the breakdown of
extracellular matrix, by other proteins from genes expressed in the TMJ, and as a
part of some genetic syndromes.
• To date , family-aggregation studies have failed to identify a genetic influence on
TMD
• Zubietta et al. reported that a common variant of the gene that codes for the
enzyme catecholO-methyl-transferase (COMT) was associated in humans with
diminished activity of pain regulatory mechanisms in the central nervous system.
Zubieta JK, Heitzeg MM, Smith YR, et al. COMT val158met genotype affects mu-opioid neurotransmitter responses to a pain stressor.
Science. 2003;299(5610):1240–1243.
EFFECT OF HERIDITARY ON SOFT TISSUES:

 (Song et al ;2019 ) investigated the influence of heritability on the

craniofacial soft tissue cephalometric characteristics of
monozygotic (MZ) twins, dizygotic (DZ) twins, and their siblings
(SIB).

 CONCLUSION:

• The nose and soft tissue chin were more influenced by

genetic factors than other soft tissues

Song J, Chae HS, Shin JW, Sung J, Song YM, Baek SH, Kim YH. Influence of heritability on craniofacial
soft tissue characteristics of monozygotic twins, dizygotic twins, and their siblings using Falconer’s method
and principal components analysis. Korean J Orthod 2019;49:3-11.
APPLICATIONS OF GENETICS:

GENETIC SCREENING

PRENATAL DIAGNOSIS

GENETIC COUNSELLING

GENE THERAPY
 GENETIC SCREENING:
• Genetic screening refers to the systematic search for
assessment of genetic status of a person who are not known to
be at a high risk individually but who may be of high risk
because of the population to which they belong
• Prenatally
• New borns
• Adults
• The goals of screening is early recognition of a disorder so that
intervention will prevent or reverse the disease process or so
that informed reproductive decisions can be made.
 PRENATAL DIAGNOSIS OF GENETIC DISEASE  

The principle aim of prenatal diagnosis is to supply at risk

families with information to make informed choices during
pregnancy.
The potential benefits of prenatal testing include:
• Provide reassurance to risk families when the result is normal
• Providing information to couples who are at risk
• Allowing the couple to prepare psychologically for the birth of
an affected baby
• Helping the physician to plan delivery, management and care of
the infant when the fetus is diagnosed with the disease
 Indications for prenatal diagnosis
• Advanced maternal age (often > 37 years)
• Previous child with a chromosomal abnormality
• Family history of chromosomal abnormality,single gene disorder,
neural tube defect, other congenital structured abnormalities
• Mid trimester ultrasound shows most severe cranial, cardiac, renal
and limb malformations
• Parental consanguinity
• Poor obsteric history (recurrent miscarraiges)

 TECHNIQUES:
o Amniocentesis
o Ultrasound
o Foetoscopy
o Cordocentesis
o Chorionic villous sampling
 TESTS OF CHROMOSOMAL
ABNORMALITIES
Two tests:

• Amniocentesis (> 16 weeks)

• Collects amniotic fluid
• Fetal cells grown and karyotype produced

• Chorionic villus sampling (CVS) (10–12 weeks)

• Rapidly dividing cells
• Karyotype within few days
AMNIOCENTESIS
GENETIC COUNSELLING:
 Communication process, which deals with human problems
associated with the occurrence of a genetic disorder in a family.
 This process
• Will help the individual / family to comprehend the medical facts,
including diagnosis, probable course of the disorder and available
management
• To understand the alternatives for dealing with the risk of recurrence
• To make the best possible adjustment to the disorder in an affected
family member

 Steps in genetic counselling

• Information gathering / diagnosis
• Risk assessment
• Information giving
• Help in decision making
 GENE THERAPY

 Gene Therapy is the technology of

introducing foreign genetic material
into a patient to correct his / her genetic defect.

 Richard Mulligan in 1979 credited to the birth of gene therapy.

 Gene therapy

Somatic gene therapy- Germ line gene therapy-

involves the insertion of a normal gene into involves the insertion of a
somatic cells such that sufficient quantities of normal gene into germ cells
the therapeutic protein will be expressed to such that it will correct the
correct the metabolic defect genetic defect and be
transmitted in a mendelian
fashion from generation to
generation.
Ex vivo gene therapy-
involves the removal of
cells from the patient, In vivo gene therapy-
the introduction of the Involves direct delivery
therapeutic gene(s) using of the therapeutic gene
viral or non-viral vectors to the target sites of
and the autologous pathology of the
transplantation of the diseased individual (eg.
gene corrected cells into i.v. infusion).
the patient.
 
GENE THERAPY OF ORTHODONTICS RELEVANCE:

1. GENE THERAPY FOR SUTURAL GROWTH

DISTURBANCES

2. GENE THERAPY IN MANDIBULAR GROWTH

3. GENE THERAPY FOR ORTHODONTIC

MOVEMENT
GENE THERAPY FOR SUTURAL GROWTH DISTURBANCES

proliferation and
FGFR 2 GENE differentiation of osteoblast
progenitor cells

MUTATED Increased proliferation of

FGFGFR 2 osteoblast progenitor cells

Premature fusion of sutures

(CRANIOSYNOSTOSIS)
GENE THERAPY IN MANDIBULAR GROWTH

 ANIMAL STUDIES: Successful gene transfer to the TMJ

with the use of recombinant Adeno–associated virus and
lentivirus .

 Use of functional appliance for mandibular deficiency-

• causes transient up regulation of a number of genes (PTHrP,

Indian hedgehog, Runx2, collagen type X, and VEGF) in
mandibular condylar cartilage.
GENE THERAPY IN ORTHODONTIC MOVEMENT

Tooth movement – Bone remodeling by osteoclasts and osteoblasts

Sources - stromal cells (osteoblasts)

hematopoietic cells (osteoclasts)

Gene therapy with OPG and RANKL to accelerate and inhibit

orthodontic tooth movement in a rat model.
(Kanzaki and colleagues, 2006)

Local gene transfer-

 RANKL ↑ tooth movement by 150% after 21 days
 OPG ↓ tooth movement by 50% after 21 days
 CONCLUSION

• The pattern of growth and development is typically the result

of an interaction between multiple genetic and environmental
factors over time
• We now know that the underlying biology of individual may
be just as important as malocclusion in the development of
treatment plan
• The influence of genetic factors on treatment outcomes must
be studied and understood in quantitative terms.
• Genome wide association studies are necessary for further
evidence based orthodontic practice
 REFERENCES:
1.Text book of craniofacial growth – Sridhar Premkumar
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3.Orthodontics Current Principles and Techniques. 4th ed. Noida: Elsevier
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7.THE CHANGING CONCEPTS OF GENETICS IN ORTHODONTICS:
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dizygotic twins, and their siblings using Falconer’s method and principal
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