GENETICS IN ORTHODONTICS WORD.docx

GENETICS IN ORTHODONTICS
PRESENTED BY
DR.SIDHARTH RAVI PILLAI
PG 1ST
YEAR
DEPARTMENT OF ORTHODONTICS
AND DENTOFACIAL ORTHOPAEDICS
GUIDED BY
DR.CH LALITHA
PROFESSOR AND HOD
DEPARTMENT OF ORTHODONTICS
AND DENTOFACIAL ORTHOPAEDICS

CONTENTS
• INTRODUCTION
• DNAAND RNA
• GENE AND GENE EXPRESSION
• MENDELIAN GENETICS
• MODES OF INHERITANCE
• TYPES OF STUDIES
• METHODS OF TRANSMISSION OF MALOCCLUSION
• THE ROLE OF HOMEOBOX GENES
• CRANIOFACIAL DEVELOPMENT
• CRANIOFACIAL DEFECTS
• GENETIC COUNSELLING
• GENE THERAPY
• CITATION
• CONCLUSION
• REFERENCES

INTRODUCTION
• Although man has always been aware that individuals differ and that
children tend to resemble their parents, the scientific basis for these
observations was only discovered during the 18th
century.
• The clinical application of this knowledge came into account in 19th
century.

IMPORTANT TERMINOLOGIES
• Gene - The basic unit of heredity. A sequence of DNA nucleotides on a
chromosome that encodes a polypeptide or RNA molecule, and so
determines the nature of an individual’s inherited traits.
• Allele - The genes responsible for contrasting characters are called
alleles.
• Locus - The location of a gene on a chromosome.
• Dominant allele - An allele that dictates the appearance of
heterozygote's.
• Recessive allele - An allele whose phenotypic effect is masked in
heterozygote's by the presence of a dominant allele.

• Haploid - Having only one set of chromosomes, example: gamete (
ovum and sperm).
• Diploid - Having two set of chromosomes, referred to as homologues ,
example : zygote.
• Genotype - The total set of genes present in the cells of an organism.
This term is often also used to refer the set of alleles at a single gene
locus.
• Phenotype - The realized expression of the genotype. The phenotype is
the observable expression of a trait (affecting an individual’s structure,
physiology or behavior) that results from the biological molecules
transcribed from the DNA.

• Heritability – The proportion of phenotypic variance attributable to the
genotype is referred to as heritability.
• Multifactorial inheritance – If the genetic variation of a particular
phenotypic trait is dependent on the simultaneous segregation of many
genes and affected by environment, it is referred to as being subject to
multifactorial inhertance.
• Polygenic variation – Genetic difference caused by the segregation of a
many genes is referred to as polygenic variation and the genes concerned
are referred to as polygenes.
• Pleiotropic – When a gene is known to affect a number of different
characters its action is said to be pleiotropic.
BRANCHES OF GENETICS
• Cytogenetics - The chromosomal study of parents in relation to their
siblings. The term is also used to describe the chromosomal
characteristics of one cell in relation to the other cells in a dividing tissue.
• Molecular Genetics - Field of study wherein genes are investigated in
relation to their chromosomal address, length, composition etc.
• Radiation Genetics - Study of radiation exposure on the structure and
function of different chromosomes and /nucleic acids.

• Reverse Genetics - Begins with the identification of a mutant gene and
ends up in the verification of its transcript. Normally, a classical genetics
starts with the observance of mutant phenotype (i.e. identification of the
protein), leading to the identification of the gene responsible for such a
phenotype.
• Immuno Genetics - deals with the hereditary and molecular aspects of
immunological reaction within an organism.
• Biochemical Genetics - involves a study of the genetic mechanisms on
the biochemical pathways.
• Malocclusion arises from the combined interactions of genetic and
environmental factors on the developmental pathway(s) involved in the
formation of the orofacial region.
• Orthodontists who gain a solid foundational understanding of genetics are
best equipped to understand why some patients develop certain
occlusions.
• To maximize the chance of successful treatment outcomes, there are two
key considerations-
• (1) properly identify the cause of the problem before attempting
treatment,
• (2) identify the factors that will influence the treatment outcome, or both.
• Knowing whether the cause of the problem is “genetic” has been cited as
a factor in eventual outcome; that is, if the problem is genetic, then
orthodontists may be limited in what they can do (or change).

BASIC STRUCTURE OF CELL
DNA
• Deoxyribonucleic acid (DNA) contains the genetic instructions used in
the development and functioning of all known living organisms.
• The DNA segments that carry this genetic information are called ‘genes’.
• The structure of DNA is a right-handed double helix. It was first
described by James Watson and Francis Crick.

• Each spiral strand, composed of a sugar phosphate backbone and attached
bases, is connected to a complementary strand by hydrogen bonding
(noncovalent) between paired bases, adenine (A) with thymine (T) and
guanine (G) with cytosine (C). Adenine and thymine are connected by
two hydrogen bonds (non-covalent) while guanine and cytosine are
connected by three hydrogen bonds.

RNA
• Ribonucleic acid (RNA) is a nucleic acid present in all living cells that
has structural similarities to DNA.
• Unlike DNA, however, RNA is most often single-stranded. An RNA
molecule has a backbone made of alternating phosphate groups and the
sugar ribose, rather than the deoxyribose found in DNA. Attached to each
sugar is one of four bases: adenine (A), uracil (U), cytosine (C) or
guanine (G).
• Different types of RNA exist in cells: messenger RNA (mRNA),
ribosomal RNA (rRNA) and transfer RNA (tRNA).
• In addition, some RNAs are involved in regulating gene expression.
• Certain viruses use RNA as their genomic material.

• In protein synthesis, mRNA carries genetic codes from the DNA in the
nucleus to ribosomes, the sites of protein translation in the cytoplasm.
Ribosomes are composed of rRNA and protein.
• The ribosome protein subunits are encoded by rRNA and are synthesized
in the nucleolus. Once fully assembled, they move to the cytoplasm,
where, as key regulators of translation, they “read” the code carried by
mRNA.
• A sequence of three nitrogenous bases in mRNA specifies incorporation
of a specific amino acid in the sequence that makes up the protein.
• Molecules of tRNA (sometimes also called soluble, or activator, RNA),
which contain fewer than 100 nucleotides, bring the specified amino
acids to the ribosomes, where they are linked to form proteins.

TRANSCRIPTION
• Transcription is the first step in gene expression. It involves copying a
gene's DNA sequence to make an RNA molecule.
• Transcription is performed by enzymes called RNA polymerases, which
link nucleotides to form an RNA strand (using a DNA strand as a
template).
• Transcription has three stages: Initiation, elongation, and termination.
• Transcription is controlled separately for each gene in your genome.
INITIATION

GENE
• The unit of inheritance is called a Gene. According to Gerstein et al, “a
gene is a union of genomic sequences encoding a coherent set of
potentially overlapping functional products”.
• The physical development and phenotype of organisms can be thought of
as a product of genes interacting with each other and with the
environment.
• The total set of genes in an organism is known as its genome.
• The current estimate places the human genome at just under 3 billion base
pairs and about 20,000 to 25,000 genes.
GENE EXPRESSION AND REGULATION
• The process by which the inheritable information in a gene, such as the
DNA sequence, is made into a functional gene product, such as protein or
RNA is known as gene expression.
• Gene regulation refers to the cellular control of the amount and timing
of changes in the appearance of the functional product of gene.
• Gene regulation gives the cell control over its structure and function.
• Inducible systems—An inducible system is off, unless there is the
presence of some molecule (called an inducer) which allows for gene
expression. The molecule is said to "induce expression".
• Repressible systems—A repressible system is one which except in the
presence of some molecule (called a core pressor), suppresses gene
expression.

• The process which occurs within a cell, triggered by a signal originating
internal or external to the cell, which results in increased expression of
one or more genes and as a result, the proteins encoded by those genes, is
called Up-regulation.
• Down-regulation is a process resulting in decreased gene and
corresponding protein expression.
MUTATION
• Alterations in the base sequence of a particular gene arise from a number
of sources of which the more important are the errors in DNA replication
and the aftermath of DNA damage. These errors are very rare.
• The error rate per site is only around 10-6 to 10-10 in eukaryotes. These
errors are called mutations.

MENDELIAN GENETICS
• The existence of genes was first suggested by Gregor Mendel. He studied
inheritance in pea plants and arrived at a conclusion that traits are carried
from the parent to the offspring by specific mechanisms.
• If both copies of the gene are identical, the individual is described as
homozygous, and if they differ, the term used is heterozygous.
• Alleles may be dominant or recessive.

MENDELIAN’S LAW OF INHERITANCE
LAW OF UNIFORMITY/DOMINANCE
• The Law of Uniformity refers to the fact that when the homozygotes
with different alleles are crossed, all the offspring in the Fl generation are
identical and heterozygous.

LAW OF INDEPENDENT ASSORTMENT
• The Law of Independent Assortment, also known as "Inheritance Law"
or Mendel's Second Law, states that the inheritance pattern of one trait
will not affect the inheritance pattern of another.

LAW OF SEGREGATION-
• The law of segregation states that during the production of gametes, two
copies of each hereditary factor segregate so that offspring acquire one
factor from each parent. In other words, allele (alternative form of the
gene) pairs segregate during the formation of gamete and re-unite
randomly during fertilization. This is also known as Mendel’s third law of
inheritance.

MODES OF INHERITANCE
• AUTOSOMAL INHERITANCE-An autosomal dominant gene is one
that occurs on an autosomal (non-sex determining) chromosome.
• As it is dominant, the phenotype it gives will be expressed even if the
gene is heterozygous. This contrasts with recessive genes, which need to
be homozygous to be expressed.
• 50% chance of children get affected.
• Both sexes are equally affected.
• All generations are affected.
• Normal children do not transmit the disease.

SEX LINKED INHERITANCE
• Sex linkage is the phenotypic expression of an allele that is related to the
sex of the individual.
• This mode of inheritance is in contrast to the inheritance of traits on
autosomal chromosomes, where both sexes have the same probability of
expressing the trait. Since, in humans, there are many more genes on the
X chromosome than there are on the Y chromosome, there are many
more X-linked traits than the Y-linked traits.
• Features of X-linked recessive inheritance were,
• Males usually only affected.
• Transmitted through unaffected heterozygous carrier females which
affects males, as well as by affected males to their obligate carrier
daughters with a consequent risk to male grand children through these
daughters.
• Affected males cannot transmit the disorder to their sons.

Y-LINKED INHERITANCE
• Y-linked or holandric inheritance implies that only males are affected.
• An affected male transmits Y-linked traits to all his sons but to none of
his daughters.

MULTIFACTORIAL INHERITANCE
• If the genetic variation of a particular phenotypic trait is dependent on the
simultaneous segregation of many genes and affected by environment, it
is referred to as being subject to multifactorial inheritance.
• If the genetic differences caused by the segregation of many genes it is
called as polygenic inheritance and the concerned genes are called
polygenes.
• Many gene loci collectively assert their influence on the trait.
• Along with genes the trait are also affected by the environment.
• Many congenital malformations and common diseases of adult life are
inherited as multifactorial traits and these are categorized as either
continuous or discontinuous.
• These disorders show a definite familial tendency, the incidence among
relatives being greater than that of the general population, but less than
that of a single gene disorder.
• Normal traits having a multifactorial influence are - intelligence, skin
colour, blood pressure, etc.
• Abnormal traits –diabetes, peptic ulcer, ischemic heart disease,
ankylosing spondylitis etc.
• Relatives have a higher incidence of these disorders, because their
genetic makeup is such, that they are more prone to the disorder.
• It is also seen that if an individual is affected by a severe form of a
disorder, the chances that someone else in the family has it, or will
develop it in the future, is greater.
Example
• Patient with bilateral cleft lip – 6% chance of another relative having it

• Patient with unilateral cleft lip – 2.5% chance.

TYPES OF STUDIES
Various studies has been employed to study mode of inheritance, which
are as follows:
I. Racial studies
II. Family Line studies
III. Twin studies

RACIAL COMPARISON METHOD
• In this method, comparison is made between various people of different
racial origin, living in the same environment. The differences between
these groups would then be attributed to ‘nature’ instead of ‘nurture’.
• The most important study, using this method was carried out by Cotton,
Tanaker and Wong (1951).
• They compared Negroes, Chinese and Nisei to standards developed by
Down’s for American Caucasians
• concluded that the position of the maxilla and mandible; size of the
maxilla, mandible and cranial base; the anterior and posterior facial
height and the gonial angle show component of genetic variability.

•
FAMILY LINE METHOD
• Many investigators have established that resemblance of facial structures
exists in varying degrees.
• The cranial base, the shape of the palate, the anteroposterior and vertical
position of premaxilla and the dimensions of the mandible have been
isolated as showing particularly close resemblance between parents and
children.

As early as 1921, family studies were conducted.
• The report of Wingate Todd in 1930 , brought to orthodontics the value of
the study of family line.
• Korkhaus (1931) and Anderson’s (1944) family line studies concluded
that mandibular protrusion showed a definite Inheritance pattern.
• Bell 1939,concluded that the restoration of masticatory function and
facial symmetry may be accomplished up to the limit of Inherited
tendency.
• Downs in 1928 reported on the inheritability of class II type of
malocclusion
• Rubbrecht in 1939 presented family pedigrees of several cases including
the nine generation Habsburg family .
• The “Habsburg jaw ” the Prognathic mandible of German royal family is
a strong indication for genetic control over craniofacial growth.
• From these family line studies it may be concluded that Cranial base,
Antero - Posterior Position of Premaxilla and Mandible show a strong
genetic component of variability.
• Overall the evidence suggests that there is Polygenic model for
inheritance of class II div I malocclusion and family provides
the clinician with valuable information in orthodontic diagnosis case
assessment and treatment planning.

TWIN STUDIES
The scientific study of human twins began in the 1870s.
• Sir Francis Galton (1822-1911) published a series of articles arguing that
heredity (nature) was stronger that environment (nurture) in determining
the respective characteristics of twins.
• “Twin studies are one of the family of design in genetics which aid in the
study of individual differences by highlighting the role of environment
and genetics on behavior.”
• Twins are invaluable in sharing these changes as they share environment
and genetics both.
• There are two different types of twins
• Monozygotic
• Dizygotic
• Monozygotic twins have identical genotype, whereas dizygotic twins are
only as alike as siblings.

Monozygotic /identical twins
• They arise from a single fertilized ovum
• Identical genetic makeup
• Same sex
• Resemble each other
Dizygotic /fraternal twins-
• They develop from two different embryos.
• Genetically alike like any other siblings.
• Can be of different sex.
• Resemblance only like siblings.

IMPORTANCE OF TWIN STUDIES
• Twin studies are done by analysing monozygotic and dizygotic twins in a
specific manner.
• In case of monozygotic twins, they have a similar genetic make-up, but
post-natally some of them have different environmental conditions.
• This helps us to study the expression of the genetic factors and at the
same time, the environmental influences on this genetic expression.
• In the case of dizygotic twins who have a similar environmental
conditions, the influence of genetic as well as the environmental factors
in the expression and development of an individual can be studied.

• Twin studies ramify into genetic, embryological, biochemical,
immunological, behavioral, anthropolpgical, psychological and
sociological aspects.
THE ESSENTIAL LOGIC OF THE TWIN DESIGN IS AS
FOLLOWS:
• MZ twins raised in a family share both 100% of their genes, and all of the
shared environment. All differences between them in this framework are
unique. The correlation observed between MZ twins provides an estimate
of role of environment and genetics .
• DZ twins have a common shared environment, and share 50% of their
genes: so the correlation between DZ twins is a direct estimate of half of
that MZ twins.
• If a condition has no genetic component, for example due to chance or
trauma, concordance rates 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.
• For discontinuous conditions, the rate in monozygotic twins, although
less than 100% will exceed the rate in dizygotic twins.
• So, far nay characteristic, the higher the monozygotic concordance, the
more important the genetic contribution and so the higher the heritability.

LIMITATION OF TWIN STUDIES
• Results from twin studies cannot be directly generalized to the general
population, due to lack of randomization; in addition, they are different
with regard to their developmental environment, as two fetus growing
simultaneously.
• Though lot of changes happened in the field of genetics over time, twin
studies today are also based on the same assumptions that were made
back in 1920s. Many of these are deeply flawed.
• Findings from twin studies are often misunderstood, misinterpreted, and
blown out of proportion, not just by the media, but even by serious
scientists who get their work published.
• Many twin registries depend on the voluntary participation of twins. This
leads to volunteer bias or recruitment bias, a special type of selection
bias, which may lead to overinclusion of identical and female twins,
resulting in overestimation of the heritability of the trait or condition
under study.

HERITABILITY OF DENTOFACIAL PHENOTYPES
Class II div I malocclusion
The investigations to determine the heritability of certain parameters in class II
div 1 malocclusion have shown that in class II patient
• The mandible is significantly more retruded than in class I patients
• The body of the mandible is smaller
• Overall mandibular length is reduced
• The cephalometric studies done on heritability of Class II malocclusion
showed that in these patients mandibular body length is small as
compared to Class I patients.
• He showed that this type of malocclusion has polygenic inheritance.(
Harris 1975)
• A large role is played by environmental factors such as habits like thumb
sucking.
•

Class II div II malocclusion
• Class II Div II with its distinct and more consistent collection of definable
morphological features can be called more of a syndrome rather than
malocclusion.
• 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.
• Often accompanied by a poorly developed cingulum on the upper incisors
and characteristic crown root angulations.
• Markovic (EJO 1992) carried out cephalometric study on 114 Class II
Div 2: 48 twin pairs and 6 sets of triplets.
• Result showed that 100% monozygotic twins were concordant and 90%
dizygotic twins were discordant.
• Mutations of genes such as Treacle that lead to less pronounce changes in
protein function or expression may be responsible for the milder cases of
mandibular retrognathia commonly seen in orthodontic practice.

HABSBURG JAW
• The Habsburg jaw, the prognathic mandible of the German royal family,
is the best known example, but dentists see repeated instances of similar
malocclusion in parents and their offspring.
• Schulze and Weise(1965) also studied mandibular prognathism in
monozygotic and dizygotic twins. They reported that concordance in
monozygotic twins was six times higher than among dizygotic twins.

Environmental factors, which may contribute to the development of mandibular
prognathism, are
• Enlarged tonsils
• Nasal blockage
• Congenital anatomic defects
• Hormonal disturbances
• Endocrine imbalances
• Posture
• Trauma / disease including premature loss of the first permanent molar
GENETIC INFLUENCE ON THE TOOTH
• The popular perception is that because of the adaptability of the
dentoalveolar region when subjected to environmental factors, local
malocclusions are primarily acquired and would be expected to have low
heritability.
• This view is reinforced and occlusion of the teeth have a stronger
environmental than hereditary influences.
• However, evidence from other studies has led to the conduction that
heredity plays a significant role in determining, among other factors,
width and length of the dental arch, crowding and spacing of teeth and
degree of overbite.

• Various developmental dental disorders ,which are under genetic
influence includes :
• Hypodontia,
• Supernumerary teeth,
• Abnormal tooth shape ,
• Submerged molars ,
• Ectopic eruption of canines .
HYPODONTIA
• The hereditary nature of hypodontia is revealed in family and twin
studies.
• A study of children with missing teeth found that up to half of their
siblings on parents also had missing teeth.
• 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) demonstrated that a mutation in MSX gene, located on
chromsome caused familial tooth agenesis.

SUPERNUMERARY TEETH
• Supernumerary teeth most frequently seen is a pre maxillary conical
midline tooth (mesiodens) with a male sex prediction and appears to be
genetically determined.
• Niswander and Sugaker (1963) have analysed the data from family
studies and have suggested that the genetics of this condition is under the
control of a number of different loci.

ABNORMAL TOOTH SHAPE
• There is substantial evidence that missing and malformed lateral incisors
may be a result of a common gene defect.
• Variations range from peg shaped to microdont to missing teeth, all of
which have familial trends, female preponderance, association with other
dental anomalies suggesting a polygenic etiology.
• Alvesalo and Portin (1969) concluded that missing and malformed lateral
incisors might be the result of a common gene defect.

ECTOPIC MAXILLARY CANINES
• Various studies in the past have indicated a genetic tendency for ectopic
maxillary canines.
• Peck et al concluded that palatally ectopic canines were an inherited trait,
being one of the anomalies in a complex of genetically related dental
disturbances.
• Previous studies have also shown an association between ectopic
maxillary canines and Class II div II malocclusion, a genetically inherited
trait.

MODE OF TRANSMITION OF MALOCCLUSION
1. REPETITIVE TRAITS
• Recurrence of single dentofacial deviation with in the immediate family
and in the progenitors.
• Seen generation after generation.
2. DISCONTINUES TRAITS
• Recurrence of a tendency for a malocclusal trait to reappear in the family
background over several generations.
• Seen in family but not in all generations.
3.VARIABLE TRAITS
• Occurrence of different but related type of malocclusion within several
generation of same family.
• Traits seen with variable expression . E.g, missing teeth, which are
commonly seen feature in some families, but the same teeth may not be
missing in different generations or with in the same generation.

HOMEOBOX GENES
• A homeobox is a DNA sequence found within genes that are involved in
the regulation of patterns of anatomical development (morphogenesis) in
human beings.
• Genes that have homeobox is called as homeobox gene.
• These can be regarded as the master genes of head and face controlling
patterning, induction, programmed cell death and epithelial mesenchymal
interaction during development of the craniofacial complex.
• Homeobox genes are a large group of genes which are highly conserved
throughout evolution of diverse organisms and are now known to play a
role in patterning the embryonic development.
• Discovered by W.GEHRING and colleagues in fruit fly drosophila
melanogaster, group of genes called homeotic genes and specify the
general body plan of the fly.

• The homeobox is about 180 base pairs long.
• It encodes a protein domain (homeodomain) which when expressed (as
protein) help in binding with the DNA.
• The homeodomain is capable of recognizing and binding to specific DNA
sequences.
• During embryogenesis, through the early recognition property of the
homeodomain, the homeoproteins are believed to regulate the entire
expression of genes and also direct the formation of many body
structures.
• The degree of sequence similarity between Drosophila and human
homeobox confirmed that the genetic control of development is universal.
• These vertebrate genes are called Hox genes and they are 39 in number.
• Humans contain Hox genes in four clusters, called :
• HOXA,
• HOXB,
• HOXC,
• and HOXD, on chromosomes 2,7,12, and 17.

HOX genes which are of particular interest in craniofacial patterning and
morphogenesis, include:
• Muscle segment (msx)
• Distal-less (dlx)
• Goosecoid (gsc)
• Otx gene.( Orthodentical gene)
• Bar class (BarH1 and BarH2)
• Paired related genes (Pax and SHOT)
• LIM homeobox gene

• The proteins coded by these homeobox genes are transcription factors
which control the transcription of RNA from the DNA template within
the cell nucleus.
• Transcription factors can switch genes on and off by activating or
repressing gene expression and therefore control other genes producing a
co-ordinated cascade of molecular events which, in turn, control
patterning and morphogenesis (Thesleff, 1995).
• Some of the important regulatory molecules in the mesenchyme, through
which homeobox genes information is expressed at the cellular level are:

PATTERNING OF FACE AND JAWS
• In humans a number of other homeobox-containing genes are expressed
in the maxillary and mandibular arches, and developing facial primordia.
These genes include
1. Msx-1,
2. Msx-2,
3. Dlx1-6
4. and Barx-1.
• Members of the Msx gene family (Msx-1 and Msx-2) are normally
expressed strongly in the neural crest derived mesenchyme of the
developing facial prominence, and there is strong evidence for a role of
these genes in specification of the skull and face.

• Targeted disruption of Msx-1 produces a number of defects in facial
structures.
There is :
• cleft palate associated with a loss of the palatine bones,
• maxillary and mandibular hypoplasia,
• and a highly penetrant arrest of tooth formation at the bud stage of tooth
development .
SUMMARY OF HOMEOBOX GENES AND THEIR FUNCTIONS
1.Msx genes –
• MSX1 expressed in neural crest cells and mesenchymeal cells of dental
papilla and follicle.
• MSX2 expressed in enamel organ and involved in signalling interactions
essential for the tooth development.
• Mutation in MSX gene leads to facial and dental abnormalities.

2. Dlx gene –
• Expressed in mesenchyme of maxillary and mandibular processes of first
arch .
3.Paired box genes-
• Pax1 in combination with Pax 2 is essential to stabilize and maintain cell
fates in craniofacial mesenchyme.
• Pax 9 is associated with development of teeth.
• Mutation of this gene leads to hypodontia , transposition etc.
CROUZON SYNDROME-
• In 1912, Crouzon described the hereditary syndrome of craniofacial
dysostosis in a mother and son.
• He described the triad of calvarial deformities,facial anomalies,
and exophthalmos.
• Crouzon syndrome is inherited as an autosomal dominant trait.
• Mutations in the FGFR2 and FGFR3 genes appear to cause increased
proliferation of the osteoprogenitor cells within the sutural mesenchyme.
This eventually leads to craniosynostosis.

SOLITARY MEDIAN MAXILLARY CENTRAL INCISOR
SYNDROME
• The presence of a single primary and permanent maxillary incisor which
is in the midline and symmetric with normal crown and root shape and
size, can be an isolated finding or can be part of the solitary median
maxillary central incisor syndrome.
TREACHER COLLINS SYNDROME
• In 1900, Treacher Collins described the essential traits of the syndrome
that bears his name.
• Treacher Collins syndrome is also known as mandibulofacial dysostosis.

DOWN’S SYNDROME
• Most common chromosomal aberration
• Down syndrome was first accurately described in 1866 by an English
physician named John Langdon Down.
Chromosomal abnormalities:
• Trisomy 21/ extra Ch 21
• 1 in 600 to 1000 live births

AMELOGENESIS IMPERFECTA
• Amelogenesis imperfecta (AI) is a group of clinically and genetically
heterogenous disorders affecting enamel formation.
• It is clinically heterogenous in that hypoplastic, hypocalcified and
hypomaturation forms have been described; and genetically heterogenous
with families exhibiting autosomal dominant, autosomal recessive and X-
linked inheritance.
• In humans, two amelogenes, AMGX and AMGY have been cloned and
mapped to the X and Y chromosome respective.
• However, it is likely that mutations in several genes may be involved in
the etiology of different forms of autosomally inherited AI.

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 principle aim of prenatal diagnosis is to supply at risk families with
information to make informed choices during pregnancy.
• The goals of screening is early recognition of a disorder so that
intervention will prevent or reverse the disease process.
INDICATIONS
1. Advanced maternal age (often > 37 years)
2. Previous child with a chromosomal abnormality
3. Family history of chromosomal abnormality
GENETIC COUNSELLING
• Genetic counselling is a 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 –
• based on history, examination and investigations
• In clinical genetics, as in all medicine, accurate diagnosis is the most
important first step in patient care.
• Risk assessment –
• As a rule of thumb the risk involved in the future generations of the
family should be assessed.
• Information giving – should be given in simple terms with proper
communication regarding the chances of recurrence, problems associated
with the disease, natural history, medical, economical, psychological and
social burden reproductive options open to the parents including prenatal
diagnosis and referral to specialist.
• Help in decision making after proper psychological assessment and
counseling

GENE THERAPY
• During the past two decades major advances have been made in the field
of the molecular pathologies of many genetic diseases (Scriver et al,
1995).
• Moreover implementation of biochemical and molecular techniques has
made accurate diagnosis, carrier detection and prenatal diagnosis for
many of these disorders a reality.
• Gene Therapy is the technology of introducing foreign genetic
material into a patient to correct his / her genetic defect.”
Gene therapy can be:
1) Somatic cell gene therapy
2) Germ line gene therapy
• Gene therapy is more easily achievable with recessive diseases that
involve a missing or defective gene product.
• Here the insertion of a normal gene will supply the missing product.
• Many recessive enzyme deficiency disorders can potentially be corrected
when only about 10% of the normal enzyme level is produced.

AN EXAMPLE OF GENE THERAPY
• Lung cancer is the leading cause of cancer related deaths annually among
both men and women in the United States.
• Development of bronchogenic carcinoma has been suggested to occur
through a series of such molecular events in which multiple genetic
abnormalities accumulate within the cells and has been called ‘‘multistep
carcinogenesis.’’
• The RAS oncogene is one of the most frequently activated oncogenes in
human cancers. Among the different RAS oncogene K- RAS is the most
common cause for lung carcinoma.
• Because oncogenes are critical in bronchogenic carcinogenesis, inhibiting
these genes has become a novel way to treat lung cancer. Oncogene
inhibition therapy can be performed using antisense, RNA interference
(RNAi), or ribozyme technologies.
• For example, expression of mutant K-ras oncogene can be eliminated by
transfusion of anti-sense K-ras RNA constructs or inserts cDNA plasmids
into human lung cancer cell lines.

GENE THERAPY IN ORTHODONTICS
• The purposes of previous gene therapy in orthodontic treatment were to
investigate the possibility of acceleration of tooth movement or reduction
of root resorption by modification of osteoclast differentiation factors
such as RANKL or OPG.
• The first attempt for gene therapy in orthodontic treatment aimed to
transfer OPG gene into periodontal tissue to reduce osteoclast activity and
inhibit tooth movement.
• The gene transfer approach using a hemagglutinating virus of Japan
(HVJ) envelope vector carrying mouse OPG messenger RNA (mRNA)
was performed in rats for 21 days of tooth movement.
• The result showed that local OPG gene transfer reduced the number of
osteoclasts and decreased tooth movement by 50% in rats in the
experimental group compared to the ones in the control group.
• The same group of investigators performed another experiment using the
same system to transfer mouse RANKL mRNA to periodontal tissue to
activate osteoclastogenesis and accelerate tooth movement in rats.
• The results showed that local RANKL gene transfer induced increased
numbers of osteoclasts and accelerated tooth movement by approximately
150% in the rats in the experimental group compared to the control group
• Gene therapy is a promising treatment option for a number of diseases.
• This approach is still in the developing process as an alternative approach
to treat deformity or disease that conventional method could not
achieved.

• Although many clinical trials have shown the efficacy of the treatment,
the technique remains risky and is still under processes of investigation to
make sure that it will be safe and do not elicit any systemic or hereditary
effects for the patients.
Evolving concepts of heredity and genetics in orthodontics
David S. Carlson Dallas, Tex (Am J Orthod Dentofacial Orthop
2015;148:922-38)
• A Major conceptual eras in genetics and orthodontics from late 19th
century through the present; key representative papers published in the
AJO-DO are listed chronologically relative to major discoveries and
conceptual advancements in the study of heredity and the field of
genetics.
•

CONCLUSION
• The orthodontic profession seems preoccupied with the problem of
demonstrating the relative importance of genetic versus environment in
the etiology of malocclusion.
• But what is more important is to understand their interaction.
• The effect of a particular environmental factor on phenotype will vary
depending on the genetic background because of the influence of the
latter on the response.
• Only with a clearer understanding of these interactions can we expect
deeper insight into the complex etiologies of various malocclusions.
• How specific genetic factors will influence a patient’s responsiveness to
environmental factors (including orthodontic treatment and the long-term
stability of its outcome) as determined by studies of genetic markers, or
gene sequences, and their impact on the proteins that they encode or
influence, should be the greatest concern for the clinician.

REFERENCES
1.Essential Medical Genetics-J.M. Connor, M.A. Ferguson-Smith
2.Genetics of Man- F. Clarke Fraser, James J. Nora
3.An Introduction To Human Genetics- 4th
Ed.- H. Eldon Sutton
4.Concepts of Genetics – Klug and Cummings
5.Orthodontics – Current Principles and Techniques – Graber Swain
6.The Heritability of Malocclusion: Part I and II. Mossey BJO 1999;
26:103-113 and 195- 203
7.The Genetic Control of Early Odontogenesis. Martyn T. Cobourne. BJO 1999;
26: 21-28
8.The Complex Genetics of Cleft Lip and Palate. Martyn T. Cobourne. EJO
2004; 26: 7-16
9.Management of Cleft Lip and Palate – A.C. H. Watson and D. A. Sell
10.Ethical Considerations Regarding the Timing of Orthodontic Treatment.
Laurance Jerrold. AJODO 1998; 113:85-90
11.Advances in Orthodontic Tooth Movement: Gene Therapy and
12.Molecular Biology Aspect by Phimon Atsawasuwan and Sajjad Shirazi.
13.Proffit WR, Fields HW, Larson B, Sarver DM. Contemporary orthodontics-
e-book. Elsevier Health Sciences; 2018 Aug 6.
14.Graber LW, Vig KW, Huang GJ, Fleming P. Orthodontics-e-book: current
principles and techniques. Elsevier Health Sciences; 2022 Aug 26

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