‘’GENES PRODUCE THE BLUEPRINT OF THE FACE’’

(NOYES 1958)

G
GENETICS AND MALOCCLUSION

K.THEJASRI
1ST YR PG
 CONTENTS
• INTRODUCTION
• HISTORY
• TERMINOLOGIES
• MENDELIAN GENETICS
• MODES OF INHERITANCE
– AUTOSOMAL INHERITANCE
– SEX-LINKED INHERITANCE
• MULTIFACTORIAL INHERITANCE
• ROLE OF HOMEOBOX GENES
• TWIN STUDIES
– HERITABILITY OF DENTOFACIAL PHENOTYPES
– HERITABILITY OF LOCAL OCCLUSAL VARIABLES
– HERITABILITY OF TOOTH NUMBER, SIZE, MORPHOLOGY, POSITION AND
ERUPTION
• CRANIOFACIAL DEFECTS
– CLEFT LIP AND CLEFT PALATE
• CONCLUSION
• REFERENCES
 INTRODUCTION

• The field of genetics emerged from the study of heredity early in the
20th century.

• Orthodontics also progressed through a series of conceptual

stages over the past 100 years based in part on the ongoing and
often circular debate about the relative importance of heredity
(nature) and the local environment (nurture) in the etiology and
treatment of malocclusion and dentofacial deformities.

Carlson.s Evolving concepts of heredity and genetics in orthodontics.Am J Orthod

Dentofacial Orthop 2015;148:922-38.
• During the past 20 years, significant advancements in
understanding the gene variants associated with dentofacial
deformities have resulted in a

• convergence of the principles and concepts in genetics and in

orthodontics that will lead to significant advancement of
orthodontic treatments.

Carlson.s Evolving concepts of heredity and genetics in orthodontics.Am J Orthod

Dentofacial Orthop 2015;148:922-38.
 GENETICS

• Genetics is derived from the Ancient Greek word genetikos.

• It is the science of genes, heredity and variation in living organisms.

• It deals with molecular structure and function of genes, patterns of

inheritance from parent to offspring, gene distribution, variation and
change in populations.

Patel.z GENETICS IN ORTHODONTICS-A REVIEW.ejpmr,2016,3(7), 539-545

 HISTORY OF GENETICS

• William Bateson a British geneticist was the first person to use the
term ―genetics (from the Greek genno, i.e. to give birth) to describe
the study of inheritance and the science of variation.

• Gregor Johann Mendel (1822-1884) often called the ―father of

genetics for his study of the inheritance of traits in pea plants.

Patel.z GENETICS IN ORTHODONTICS-A REVIEW.ejpmr,2016,3(7), 539-545

 • Ray E Stewart, a medical geneticist, listed malocclusion as the
most common hereditary deviation in dentistry followed by
periodontal disease and dental caries.

• In 1836 Frederick Kussel reported that malocclusion both

skeletal and dental can be transmitted from one generation to
another.

• He also reported that chromosomal defects account for about

10% of all malocclusions.

Patel.z GENETICS IN ORTHODONTICS-A REVIEW.ejpmr,2016,3(7), 539-545

• Rediscovery of Mendel’s laws (de Vries, 1900)

• Chromosome as unit of heredity (Sutton, 1904)

• In 1944 ,Oswald Avery showed genes are composed of

deoxyribonucleic acid (DNA).

• James Watson and Francis Crick gave the most significant

achievement in 1953 which was the physical structure of DNA.

• 1st identified chromosomal abnormality, trisomy 21 (1959).

Carlson.s Evolving concepts of heredity and genetics in orthodontics.Am J

Orthod Dentofacial Orthop 2015;148:922-38.
 CYTOLOGY

• The term cell was first coined by Robert Hook in 1665. All
living organisms from bacteria to the tree, Amoeba to man has
a common unit of structure – The Cell.

• Cell can be defined as “Basic structure and functional unit of

an organism”
 CELL STRUCTURE

• It is made up of
different organelle
that is the cellular
cytoplasm,
Endoplasmic
Reticulum's,
Ribosome's,
Mitochondria,
Nucleus etc.
 CHROMOSOMES
• IN a resting cell chromosomes are not visible under a light
microscope as their chromatin material is highly dispersed.

• During cell divison chromatin network in the nucleus becomes

condensed into a number of chromosomes.
• Each chromosome bears on itself a very large number of
structures called genes.

• Chemically gene is composed of DNA.

• Structural gene can be defined as a segment of DNA which

contains the information for the synthesis of an enzyme

• Thus gene is nothing but a set of instructions for making proteins.

 STRUCTURE OF DNA

• The structure of DNA was discovered by Watson and Crick in 1953.

DNA in a chromosome is in a form of very fine firbres.

• Each fibre consists of 2 strand which are parallel to each other but
running in anti parallel direction.
 STRUCTURE OF DNA
• It is made up of molecules called nucleotides.

• Each nucleotide contains a phosphate group, a sugar group and a

nitrogen base.

• The four types of nitrogen bases are

adenine (A), thymine (T), guanine (G) and cytosine (C).

• Both the opposite strands are linked by purine and pyramidine
bondings.

• This purine and pyramidine is known as Complimentary Base

Pairing.

• Bonding is always specific between the 2 opposite strand

adenine with thymine and cytosine always with Guainine.
 MENDELS EXPERIMENTS ON PEA PLANTS

• Gregor Jhoann Mendel, an Austrian

monk, is considered the “father” of
genetics.
• He advanced the field significantly by
performing a series of cleverly designed
experiments on garden peas.
• Mendel published the results of his experiments in 1865.

• It is one of the ironies of biological sciences that his discoveries

, which still form the foundation of genetics, received no
recognition for 35 years.

• In his breeding experiments Mendel studied contrasting

characters in the garden pea, for example tallness.
• Experiment of Mendel: Mendel
selected stem height as a trait to be
studied. He made crosses between
tall and dwarf plants. The plant with
which he started his experiment
formed the parental generation.
• Mendel’s Principle of Dominance and Recessive: It states that
“One factor in a pair may prevent the expression of the other
factor.” In other words the expression of the dominant
character and suppression of the recessive character in F1
hybrids is the principle of dominance.
• Law of Segregation: It states that “Whenever a pair of
factors for a character is brought together in hybrid the factor
segregate or separate during the formation of gametes.”
Hence each gamete receives a single ‘pure’ factor either
dominant or recessive.
 Explanation of Law of Segregation:

• Mendel used T for dominant and t for recessive.

• According to Mendel pure breeding tall plant of parental

generation contained 2 identical factor for tallness TT, 2
identical factor for dwarfness tt.
• All factors Tt will segregate.

• This means 50% of the total number of Gamete is T and the

remaining 50% is t.

• When Gamete carrying these factors fuse to form zygotes,

there will be 3 combination, TT, tt and Tt.

• TT and Tt produce small plants, tt form dwarf plant.

• Thus a total of ¾ tall and ¼ dwarf. This is the 3:1 ratio

observed by Mendel.
Terminologies:
Genotype:
• The Genetic constitution of an individual.
Phenotype:
• The manifested character of an individual.
Alleles:
• Alternate form of Genes which exist are called Alleles.
• Homozygous: When both the alleles are identical in the locus of
a pair of chromosome it is called Homozygous.

• Heterozygous: When both the alleles are not identical in the

locus of pair of chromosome it is called Heterozygous.

• Recessive Gene: It is a Gene which fails to express itself in the

presence of its contrasting dominant Gene, in a Heterozygote.

• Dominant Gene: The Gene which expresses itself in the

presence of its contrasting dominant Gene, in a Heterozygote.
• 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.

• EXAMPLE: 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, while the absence of all four occasionally found in carriers
of this gene, is zero expressivity
 Mitosis:
• It is the cell division in which replication of chromosome are
distributed to daughter cells in such a way that they come to
have exactly the same number of chromosomes as the parent
cell.

• Sequential stages include prophase, metaphase, anaphase,

telophase.
• Meiosis: It is defined as “All division occurring in diploid cells,
in which the daughter cells receive only one haploid number of
chromosomes.

• It is a special form of cell divison that occurs in the fetal, adult

ovary and postpubertal testis.
• During anaphase of meiosis an error in cell divison called Non-
disjunction results in a reproductive cell with an abnormal number
of chromosomes.

• If this occurs egg or sperm cell may gain an extra copy of

chromosome and contributes to the genetic makeup of a child,
the child will have an extra chromosome in each of the body cells.

• Non-disjunction of chromosomes is a common error in human

meiosis resulting in trisomy of individual chromosomes.

• EXAMPLE: Downs syndrome-Trisomy 21. Trisomy 18-Edwards

syndrome,Trisomy 13-pataus syndrome.
EDWARDS SYNDROME

Mental retardation
Brachycephaly
Micrognathia
Hypodontia
CLP
PATAU SYNDROME

Mental retardation
Microcephaly
Cleft lip/palate
Micrognathia, small eyes
DOWNS SYNDROME
 MUTATIONS
• Mutation refers to permanent changes in DNA.
Types of mutations
• Point mutations : Change in the single base pair
1. Silent mutations
2. Missense mutations
3. Nonsense mutations

• Deletions and insertions: One or more base pairs are deleted or

inserted in the DNA sequence.

• Frameshift mutation: if the deletion or insertion of base pairs is

not in the mutiple of three, all the downstream codons are
altered and markedly changed protein product results.
• SILENT MUTATIONS:
DNA mutation that do not result in a
change to the aminoacid sequence of a protein.

• NONSENSE : point mutation in a sequence of DNA that results

in a premature stop codon resulting in
nonfunctional protein product.
 MISSENSE MUTATION
• Sickle-cell disease is caused by a single
point mutation (a missense mutation) in the beta-hemoglobin
gene that converts a GAG codon into GUG, which encodes the
amino acid valine rather than glutamic acid.

•
MODES OF INHERITANCE
when the mother alone is
the carrier of a defective gene
associated with a disease
Her children will inherit the disorder
as follows:
•Of her daughters and sons: 50% will
have the disorder, 50% will be
completely unaffected.
•Children of either sex have an even
chance of receiving either of their
mother's two X chromosomes, one of
which contains the defective gene in
question.
When the father alone is the carrier
of a defective gene associated with
a disease or disorder
His children will inherit the disorder
as follows:
•Of his daughters: 100% will have
the disorder, since all of his
daughters will receive one copy of
his single X chromosome.
•Of his sons: none will have the
disorder; sons do not receive an X
chromosome from their father.
• X-linked recessive traits are expressed in all
males, but only in those females which are
homozygous for the recessive allele.

• For example, an X-linked recessive allele in

humans causes hemophilia.

• Hemophilia is much more common in males than

females because males are hemizygous—they
only have one copy of the gene in question—and
therefore express the trait when they inherit one
mutant allele.

• In contrast, a female must inherit two mutant

alleles, a less frequent event since the mutant
allele is rare in the population .
 MULTIFACTORIAL INHERITANCE

• In contrast to single-gene inheritance, either autosomal or sex-

linked, the pedigree pattern does not afford a diagnosis of
multifactorial inheritance.

• In multifactorial traits, the trait(disease) is determined by the

interaction of a number of genes at different loci, each with a
small, but additive effect, together with environmental factors.
 MONOGENIC
TRAITS

MULTIFACTORIAL
TRAITS
 DISCONTINUOUS MULTIFACTORIAL TRAITS

• There is an underlying scale of continuous variation of liability to develop

the condition resulting from a combination of all the genetic and
environmental influences involved.

• The condition is present only when the liability exceeds a critical

threshold value, and the greater the level of liability beyond the threshold
the more severe the disease.
• Cleft lip and palate is a congenital malformation inherited as a
multifactorial trait.

• In the mildest form the lip alone is unilaterally cleft, whereas in

the most severe form the lip is bilaterally cleft and the palatal
cleft is complete.
 DISCONTINUOUS MULTIFACTORIAL TRAITS

• For parents (first-degree relatives) of an affected child the liability curve is shifted
to the right -increased frequency of this malformation amongst parents and other
first-degree relatives.
• With each further degree of relationship the liability curve moves back a step
towards the general population position, with a corresponding reduction in the
incidence.
• The more severe the malformation in the affected child, the more the parents’
liability curve is shifted to the right and the higher the incidence in relatives.
 CONTINUOUS MULTIFACTORIAL TRAITS

• Many normal human characteristics are determined as

continuous multifactorial traits.

• These traits by definition have a continuously graded distribution.

• Thus, for height there is a range from the very tall to the
markedly short with the mean of 169cm in English males
(Connor and Ferguson Smith, 1993).

• The majority of individuals are centred around the mean.

• It is important to put malocclusion in context in this regard—
malocclusion should be regarded not as abnormal or as a
disease, but as a variation of occlusion in a continuous multi-
factorial trait.

• Orthodontists may try to impose a threshold according to

treatment need or complexity of mechanical treatment.
HOMEOBOX GENES

• Genes that have a homeobox are called homeobox genes and

form the homeobox gene family.

• Homeobox genes are highly conserved throughout the evolution

of diverse organisms and are now known to play a role in
patterning the embryonic development.
 HOMEOBOX GENES
• Edward Lewis was the first person to identify the Homeotic Genes
in Dorsophilia melanogaster (Fruit fly) , which help in controlling
the developmental response of a group of cells along the body’s
antero-posterior axis.

• Nueral crest cells are important in in facial development.

• Their migration and division is under the control of homeobox

genes ,which endows nueral crest cells with a positional identity,
which mediates aspects of craniofacial morphogenesis and
patterning.
• Regarded as master genes of the head and face controlling
patterning ,induction, programmed cell death, and epithelial
mesenchymal interaction during craniofacial development.

• It is the rhombencephalic derived neural crest that will give

rise to the majority of the branchial arch mesenchyme.

• It is clear, therefore, that the neural crest derived from the

hindbrain is essential for normal formation of the face and
neck.
• The hindbrain itself is known to be a segmented structure
composed of eight subunits called rhombomeres (Lumsden
and Keynes, 1989).

• Rhombomeres are important segmental units of organization,

which have distinct morphological properties.
• Neural crest cells destined for the first branchial arch migrate
essentially from rhombomeres 1 and 2, while those for the
second and third arches migrate from rhombomeres 4 and 6,
respectively.

• The even numbered rhombomeres (2, 4, and 6) contain the exit

points for cranial nerves V, VII, and IX, nerves that will innervate
branchial arches 1, 2, and 3.
 HOM GENE
ABBREVIATIONS
lab, labial;
pb, proboscipedia;
Dfd, Deformed;
Scr, Sex combs
reduced;
Antp, Antennapedia;
Ubx, Ultrabithorax;
abd-A, abdominal-A;
Abd-B, Abdominal-
B.

• Genomic organization of Drosophila HOM genes and mammalian Hox genes.

Schematic representation of the Drosophila homeotic complex (HOM-C), the four
human Hox complexes and a hypothetical ancestral homeotic complex are
displayed showing their possible phylogenic relationships. Each gene is
represented by a colored box.
The subfamilies of Hox genes, which are of particular interest in
craniofacial patterning and morphogenesis include

(muscle segment) Msx1 and Msx2

(Distalless) Dlx

(Orthodontical ) Otx Transcription

factors
(Goosecoid) Gsc

(sonic hedgehog) Shh

TRANSCRIPTION
DNA RNA
• Transcription factors can switch genes on and off by activating or
repressing gene expression, and therefore control other genes,
producing a coordinated cascade of molecular events which ,in turn
control patterning and morphogenesis.

• At a cellular level this control is expressed through two main groups

of regulatory proteins growth factor family, steroid/thyroid/retinoic
acid superfamily.
 ODONTOGENIC HOMEOBOX CODE

• Odontogenic homeobox genes provide a homeobox code that

specific regions of the developing jaws to assume odontogenic
potential.

• Various odontogenic homeobox genes identified were:

• MSX genes MSX1, MSX2

• DLX genes DLX1, DLX2

• BARX genes BARX1,BARX2

 MSX GENES

• MSX is an important gene involved in tooth formation.

• MSX stands for muscle segment homeobox gene.

• Mutation of this gene has been associated with facial and dental
abnormalities.

• MSX-1 gene is expressed in migrating neural crest cells and later,

in the mesenchymal cells of dental papilla and follicle.

• MSX-2 genes are involved in signaling interactions, which are

essential for the tooth development.
• Three MSX genes in mammals are MSX1-MSX3.

• MSX1 knockout in mice caused—clefting, aberration in tooth

development, missing teeth and deficiency of alveolar bones.

• MSX2 knockout—multiple inductive failures and early death.

• The combination of MSX1 and 2 knockout—causes severe

aberration of development of the skeleton and some other
organs, severe skeletal deficiencies in calvaria, teeth and
alveolar bone.
• Vastardis et.al studied the cause for selective tooth agenesis in
humans where missense mutation occurred in the msx1.

• Replacement of arginine with proline (Arg 196 Pro mutation) in

the homeodomain of MSX-1.

• Missing maxillary laterals,man 2nd premolars –defects in

msx1,msx2.
• Lidral 2002 concluded that a mutation in MSX-1 gene in
chromosome 4 has been identified as the causative factor for
oligodontia involving the absence of all second premolar and
third molars.

• Missing 1st molar and 2nd molars have been linked with a
substitution mutation of MSX-1 gene.
 DLX GENES

• DLX genes are expressed in the migrating neural crest cells and
in the first brachial arch.

• DLX stands for distal-less homeobox

• Targeted mutation of DLX-1 & DLX-2 reveals that they regulate

proximal first arch structures.

• Expression of DLX-1 and DLX-2 in the maxillary and the

mandibular arch mesenchyme is restricted to the proximal regions
where the future molar teeth will develop.
 BARX GENES

• BARX stands for Bar class Homeobox genes.

• BARX-1 is expressed within the ectomesenchyme of the first

branchial arch.

• BARX-2 - group of homeodomain transcription factors.

• locus 11q25 –Dorsophilia melanogaster.

• BARX-1 (along with DLX-2) is expressed in the region of future

molar development.
• BARX1 expression is absent in the anterior regions.

• As tooth development proceeds, BARX-1 expression becomes

localized exclusively to the mesenchymal regions around the
developing molars.

• Mutation of these genes could be associated with facial and

dental anomalies.
 PAX GENES

• PAX Genes- Paired-box homeotic gene.

• There are nine PAX genes organized into four groups (Pax1 to Pax9).

• Of these genes, Pax9 is associated with the development of teeth.

• Mutations in this gene results in conditions such as missing man 2nd

premolars and central incisors, transposition, etc.

• Neubuser et al, found that PAX-9 transcription factor is associated with

the genetic mechanism for tooth displacement anomalies, such as
palatally displaced canines and canine transposition.
 HEDGEHOG GENES

• Sonic hedgehog gene is expressed in the epithelial thickenings of the

tooth forming regions.

• SHH along with bone morphogenetic protein (BMP-4) determines the

position of future forming tooth germs.

• SHH is necessary for the initiation of tooth development, epithelial

signaling and cuspal morphogenesis.
 PATTERNING THE MIDLINE

• Hedgehog morphogenes are involved in the control of left-right

asymmetry, the determination of polarity in the central nervous
system, somites and limbs, and in both organogenesis and the
formation of the skeleton.

• In the vertebrate embryo, SHH encodes a signaling peptide which is

involved in a number of well-characterized developmental signaling
centers.
• Mutations of SHH in the mouse and human leads to profound
abnormalities in craniofacial morphogenesis.

• Loss of SHH produces defective patterning of the neural plate

resulting in holoprosencephaly, a failure of cleavage in the midline of
forebrain and cyclopia.

• Later in development, SHH is expressed in the ectoderm of the

fronto-nasal and maxillary processes and has been shown to be
essential for their normal development.
• By manipulating developing chick embryos, it has been shown that a
transient loss of SHH signaling in these regions of the developing face
can result in defects analogous to hypotelorism and cleft lip/palate,
which are characteristic features of the milder form of
holoprosencephaly.

• In contrast, excess SHH leads to mediolateral widening of the

frontonasal process resulting in hypertelorism. In severe cases, this
can lead to facial duplication.
 PALATE FORMATION

• Interestingly, it was recently shown that sonic hedge hog (SHH) and the
FGFR were also expressed in the early palatal epithelium and appear
to be induced by FGF10.

• When this pathway was disrupted in transgenic animals, the palatal

processes failed to grow.
 GOOSECOID

• Goosecoid - homeobox-containing transcription factor known to be

ultimately responsible for the organization of the complete body axis in
the early embryo.

• However, when goosecoid was knocked out in transgenic mice they

formed a body axis normally, but exhibited a number of craniofacial
defects.

• In wild type mice, goosecoid transcripts had been detected at the later
stages of development in the osteogenic mesenchyme of the developing
mandible, tongue and middle ear.
• In mutants, the mandible was hypoplastic, and lacked coronoid and
angular process, whilst there were defects in several bones, including
the maxillary, the palatine, and the pterygoid.

• As a homeobox containing transcription factor, it would appear that

goosecoid is involved in essential inductive tissue interactions during
the formation of the head.
 ENDOTHELIN

• Endothelin-1 which encodes a vasoactive peptide expressed in

vascular endothelial cells and is thought to play a role in the regulation
of blood pressure.

• Mice with targeted disruption of endothelin-1 have no abnormalities of

their cardiovascular system, but do have a marked reduction in tongue
size, micrognathia and cleft palate.
 GROWTH OF CONDYLAR CARTILAGE

• Fibroblast growth factor 2 (FGF-2), Insulin-like growth factor 1 (IGF-1),

reported to be present in the MCC and its type 1 receptor (IGF-1R) has
been localized to the chondroprogenitor (prechondroblastic) zone of
MCC.

• With more specific understanding of the characteristics of the "germinal

cells" or those which proliferate in the MCC, it might be possible to effect
a profound increase in their mitotic capabilities leading to a therapeutic
increase in mandibular growth.
 TWIN STUDIES

• In1870s Sir Francis Galton (1822-1911) published a series of

articles arguing that heredity (nature) was a stronger factor than
environment (nurture) in determining the respective
characteristics of twins.

• Twin study is one of the most effective methods available for

investigating genetically determined variables of malocclusion.
• Concordant: if both the twins show a discontinuous trait.

• Discordant: if only one shows the trait.

• Monozygotic twins(identical): Have identical genotypes & share

100% of their genes.

• Dizygotic twins(fraternal): Share 50% of their genes. Only as alike

as siblings.
• In cleft studies, twin concordance rate for (Connor and Ferguson-
Smith, 1993).

Monozygotic Dizygotic

• CL(P) 35% 5%

• CP 26% 6%

• This reflects the heritability of the condition: the higher the

MONOZYGOTIC CONCORDANCE, the more important the
genetic contribution, and so the higher the heritability.
• Horowitz et al. (1960) studied fraternal and identical adult twin
pairs using only linear cephalometric measurements, and he
demonstrated highly significant hereditary variations in the

1. anterior cranial base,

2. mandibular body length,

3. 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.
• Fernex et al. (1967) found boys to show more similarities 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 genetic 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.
• Litton et al. (1970) concluded that siblings usually show similar
types of malocclusion and examination of older siblings can
provide a cIue to the need for interception and early treatment of
malocclusion.

• Kraus et al. (1959). Their study involved superimposition of

lateral cephalograms of a sample of identical twins and showed
that many bony contours are in almost perfect concordance. This
applied equally to contours across sutures and to individual bony
contours such as the mandible.
 CLASS 2 DIV 1 MALOCCLUSION

• Extensive cephalometric studies by (Harris, 1963, 1975) have

shown that, in the Class II patient, the mandible is significantly
more retruded than in Class I patients, with the body of the
mandible smaller and overall mandibular length reduced.

• They also suggested a 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), Rubbrecht (1930), Trauner (1968) and Peck et al.
(1998).
• A study by Markovic (1992) has showed that in Monozygotic
twin pairs, 100 per cent demonstrated concordance for the Class
II division 2 malocclusion, Whilst almost 90 percent of the
dizygotic twin pairs were discordant.

• This suggests strong evidence for genetics as the main

aetiological factor in the development of Class II division 2
malocclusions.
 CLASS III MALOCCLUSION
• Most famous example of a genetic trait in humans passing
through several generations is the pedigree of the so-called
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.
• Schulze and Weise (1965) also studied mandibular
prognathism in monozygotic and dizygotic twins.

• Concordance in monozygotic twins was six times higher than

among dizygotic twins.

• Familial studies of mandibular prognathism are suggestive of

heredity in the aetiology of this condition (Castro, 1928; Downs,
1928; Keeler, 1935; Moore and Hughes, 1942; Gottlieb and
Gottlieb, 1954).
 HERITABILITY OF LOCAL OCCLUSAL VARIABLES
• Lundstrom (1948) studied 50 pairs of monozygotic and 50 pairs
of dizygotic twins Heredity played a significant role in
determining,

1. width and length of the dental arch,

2. crowding

3. spacing of the teeth,

4. degree of overbite.

Hu et al. (1992) also reported familial similarity in dental archform

and tooth position.
 GENETIC INFLUENCE ON TOOTH NUMBER, SIZE,
MORPHOLOGY, POSITION, ERUPTION.

• Twin studies have shown that tooth crown dimensions are

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

• Hypodontia involving the 3rd molars, 2nd premolars and lateral

incisors teeth shows a familial tendency.

• Markovic(1982) found high rate of concordance among

monozygotic twins for hypodontia.
 SUPERNUMERARY TEETH

• The most common type of supernumerary

teeth is a mesiodens.

• These are more commonly present in parents and siblings of

patients who present with it.

• Its inheritance does not follow a simple Mendalian pattern

(Brook, 1984; Mercuri and O'Neill, 1980; Mason and Rule,
1995).

• Evidence from twins with supernumeraryteeth also supports

the polygenic inheritance(Jasmin et al., 1993).
 ABNORMAL TOOTH SHAPE
• Abnormalities in the lateral incisor region varies from peg shaped to
microdont to missing teeth.

• All of which have familial trends,

• Female preponderance.

• Association with other dental anomalies, such as other missing teeth,

ectopic canines, and transposition, suggesting a polygenic aetiology.

• Alvesalo and Portin (1969) provided substantial evidence supporting the

view that missing and malformed lateral incisors may well be the result of
a common gene defect.

• Carabelli trait also seem to be strongly influenced by genes as evidenced

by an Australian twin study (Townsend and Martin, 1992).
 ECTOPIC MAXILLARY CANINES

• Studies have indicated a genetic tendency for ectopic maxillary

canines (Zilberman et at., 1990).

• Peck et al. (1994) concluded that palatally ectopic canines were

an inherited trait, often occurring in combination

with missing teeth, tooth size reduction,

supernumerary teeth.

• Studies have also shown an association between ectopic

maxillary canines and Class II division 2 malocclusion, a
genetically-inherited trait.
SUBMERGED PRIMARY MOLARS

• Mandibular arch (Kurol, 1981).

• The siblings of affected children are likely to also be affected in

about 18 per cent of cases,

• In monozygous twins there is a high rate of concordance (Helpin

and Duncan, 1986) was shown.

•
 MIDLINE DIASTEMA

• Familial occurence(schmitt 1982, neville etal 1997, harris &

johnson 1991)

• Studies of monozygotic twins have revealed high

concordance rate, suggesting heredity to be a major factor.

• Shashua and artun(1997) reported a genetic predisposition of

the trait.

• Environmental factors
EXTERNAL APICAL ROOT
RESORPTION

• External apical root resorption (EARR) is a common clinical

complication of orthodontic treatment.

• Although EARR may occur in any or all teeth, it most often involves
the maxillary incisors.

• Seven to 13% of individuals who have not had orthodontic treatment

show 1 to 3 mm of EARR on radiographs.

• Severe EARR, which is root loss of more than 5 mm, has been
reported to occur in 2% to 5% of patients treated with orthodontics.
 EXTERNAL APICAL ROOT
RESORPTION

• Al-Qawasmi and coworkers in their study found suggestive

evidence of linkage between EARR of maxillary central incisors
and a polymorphic marker D18S64.

• This marker lies close to the TNFRSF11A gene suggesting that

this locus contributes to the susceptibility to EARR.

• The TNFRSF11A gene codes for RANK, an essential signaling

molecule in osteoclasts differentiation and function.

• IL-1B polymorphism accounts for 15% of the total variation seen

for EARR seen in the maxillary central incisor.
CRANIOFACIAL DEFECTS

CLEFT LIP/PALATE
HUMAN GENOME PROJECT
• A recent initiative by Yamada et al (1998 ) entitled ‘The oral
and craniofacial genome project’

• The objective is to build up c DNA libraries with a view of

discoverering the genes for normal and abnormal oral and
craniofacial development.
• On the genetic side the advent of diagnostic techniques in the
field of molecular genetics make it possible to identify relevant
morphogenes or markers such as those for mandibular
prognathism or to influence the development of malocclusion,

• Example: Crowding could be eliminated by selective

manipulation of the homeobox gene responsible for initiation of
tooth formation and patterning of the dentition. However it is a
theoretical concept than a practical proposition.
 Sasaki.y .The P561T polymorphism of the growth hormone receptor
gene has an inhibitory effect on mandibular growth in young children.
European Journal of Orthodontics.2009;31(5):536-541.

• At position 1777 in GHR, a transversion of amino acid from cytosine to

adenine changed codon 561 from proline to threonine (P561T), affecting
the cytoplasmic domain of the GHR.
• Study was to assess whether P561T missense mutation affects mandibular
growth during early childhood.
• The difference in mandibular growth between P561T heterozygous and
wild-type individuals was analysed by cephalometric measurements during
childhood.
• The subjects included 33 children with mandibular protrusion and 27
normal children.
• Genomic DNA extracted from buccal epithelial cells was genotyped for
the P561T heterozygous mutation with a molecular analysis (polymerase
chain reaction—restriction fragment length polymorphism method)
• CONCLUSION:P561T heterozygous mutation in the GHR gene functions
as an inhibitory factor in the process of mandibular growth.
 Yamaguchi.T.et,al.Growth hormone receptor gene variant and
mandibular height in the normal Japanese population. Am J
Orthod Dentofacial Orthop 2001;119:650-3.

• Evaluated the relationship between craniofacial morphology and the

Pro561Thr (P56IT) variant in the growth hormone receptor gene (GHR),
which is considered to be an important factor in craniofacial and skeletal
growth.
• Subjects:unrelated individuals in a normal Japanese population
and consisted of 50 men and 50 women.
• Genomic DNA extracted from whole blood, the GHR gene P56IT
variant was detected by the polymerase chain reaction–restriction
fragment length polymorphism method.
• 5 linear measurements from lateral cephalograms were examined for
evaluation of craniofacial morphology.

•CONCLUSION: normal Japanese

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.
Xue F., Rabie A. B. M., Luo G. Analysis of the association of COL2A1 and IGF-
1 with mandibular prognathism in a Chinese population Orthod Craniofac
Res 2014.
• case–control association analysis to determine whether the
candidate genes COL2A1 and IGF-1 are susceptibility genes for
mandibular prognathism (MP).

• Candidate genes of interest, IGF-1 and COL2A1, are located within

the regions 12q23 and 12q13, respectively.
• Methods
• The individual SNPs and the relevant haplotypes were analyzed and
tested for an association with MP, to identify genes potentially
associated with MP.
• Conclusion – An association between polymorphism in the
COL2A1 gene and MP was observed.
• The results suggested that the COL2A1 gene could be a new
susceptibility gene for use in the study of genetic risk factors
for MP.
 FUTURE IMPORTANCE OF GENETICS IN ORTHODONTICS.

• orthodontic biomechanics and appliances undoubtedly will

continue to be the main approach for treatment of malocclusions
and dentofacial deformities.

• The primary change will be seen in the diagnosis and treatment

planning related to options for the most effective way to treat
malocclusions and dentofacial deformities, from dental
irregularities to major jaw discrepancies, on a patient-by-patient

basis.
• Orthodontists in the future will also take samples of saliva or other bodily
fluids for assessment of biomarkers for gene variants that might affect,
positively and negatively, orthodontic treatment, whether for simple
tooth movement and post orthodontic stability or for dentofacial
orthopedic treatment of a developing malocclusion and dentofacial
deformity.
• Current orthodontic research in modern genetics that will lead
to greater understanding not only of dentofacial development
and growth but also of the highly significant advances that will
be made toward the most efficacious approaches for treatment
of malocclusion and dentofacial deformities for orthodontic
patients.
 CONCLUSION

• In clinical orthodontics it must be appreciated that each

malocclusion occupies its own distinctive slot in the genetics-
environmental spectrum and therefore the diagnostic goal is
to determine the relative contribution of genetics and the
environment. Greater the genetic component , less will be the
successful outcome by means of orthodontic intervention.
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