Genetics and orthodontics /certified fixed orthodontic courses by Indian dental academy

GENETICS AND ITS ROLE IN
ORTHODONTICS
www.indiandentalacademy.com
INDIAN DENTAL ACADEMY
Leader in continuing dental education

CONTENTS
 INTRODUCTION
 DEFINITIONS
 MENDELISM
 HUMAN CHROMOSOME
 MODES OF INHERITANCE
 monogenic
 multifactorial
 TWIN STUDIES
 MUTATIONS
 CHROMOSOMAL ABNORMALITIES
 ROLE OF GENES IN MALOCCLUSION

Orthodontics and genetics
 Malocclusion is a manifestation of genetic
and environmental interaction on the
development of the orofacial region.
 Orthodontists are interested in genetics to
understand why a patient has a particular
occlusion.

 Determination of the actual level of genetic
contribution - significant effect on prognosis
& treatment planning.
 If malocclusion is a genetically controlled
phenomenon- only genetic counseling &
early intervention with appliances may be of
some help.

 So it is important to find out whether
malocclusion is under genetic or
environmental influences.

Terms
Genetics -
• The branch of biology which deals primarily
with the principles of heredity & variation &
secondarily with the role of environmental
factors as they interact with genes in the
development of an individual.

Heredity -
• It can be defined as that force of nature which
permits the transmission of characteristics of a
species from generation to generation .
 Gamete - a germ cell (sperm or ovum ) containing
haploid number of chromosomes .
 Chromosomes - thread like deep staining bodies
situated within nucleus

 Chromatin - it is the name given to the material of
which chromosomes are made
 Gene - is a part of DNA molecule which directs the
synthesis of specific polypeptide chain.
 Allele- alternative forms of a gene found at same
locus on homologous chromosomes.

 Autosome- is any chromosome other than the sex
chromosome.
 Genotype - genetic constitution of an individual
 Phenotype -it is the final product or all the
observable characteristics of an individual.
 Depends on genotype and environmental factors .

 Trait - any detectable phenotypic property or
character.
 Linkage - two genes situated close together
on same chromosome are said to be linked.

 Heritability-proportion of the phenotypic
variance attributable to genotype.
 Genome- contains the entire genetic content
of chromosomes present within a cell or an
organism.

 Multifactorial inheritance- if the genetic
variation of a particular phenotypic trait is
dependent on the simultaneous segregation
of many genes & affected by environment.

Development of genetics
 Mendelism - Gregor Johann Mendel.
 He made his discoveries by analysis of results after
crossing varieties of Garden pea (Pisum sativum)
round or wrinkled seeds
tall or dwarf plant
yellow or white flowers
He crossed varieties differing only in one pair of these
characteristics

In his monohybrid experiments he found the genotypic
ratio of 1 when he crossed pure varieties with
opposing traits.
R R
r Rr Rr
r Rr Rr

R r
R RR Rr
r Rr rr
Crossing the second generation in which he obtained
plants with only round seeds , he obtained genotypic
Ratio of 1:2:1

Dihybrid cross:
When he crossed the second generation of plant variable in two
characteristics he obtained a phenotypic ratio of 9:3:3:1
SY Sy sY sy
SY SSYY SSYy SsYY SsYy
Sy SSYy SSyy SsYy Ssyy
sY SsYY SsYy ssYY ssYy
sy SsYy Ssyy ssYy ssyy

Mendel’s laws:
 First law-a unit of genetic information is
transmissible unchanged from generation to
generation.
 Second law- alternate forms of the gene
must segregateduring gamete formation and
recombine independently in the offspring to
provide ratio of 1:2:1.

 Third law or Law of Independent assortment –
independent assortment occurs only when genes
affecting different characters are on different
chromosomes. In other words genes that are not
alleles are distributed to gametes independently to
each other.

 Law of Uniformity –when 2 homozygotes with
different alleles are crossed all of the off springs of
first generation are identical heterozygotes.
 Law of Seggration –each individual possess 2
factors which determine specific characteristic, a
parent transmits only 1 of these factors to any
particular off spring.It is purely a matter of chance
which of the 2 factors get transmitted.

Human chromosome
 These are thread like structures located in the cell
nucleus.
 Each species has a specific number of chromosomes
 Humans have 23 pairs or 46 .
 22 pairs are autosomes ,1 pair is sex chromosomes
XX/XY
 Chromosomes vary in shape depending on the
position of centromere

 Individual chromosomes differ not only in position of
centromere but also in their overall length(amount of
DNA )
 Human chromosomes are divided into 7 groups
depending on size ,position of centromere, presence
or absence of satellites
 If the allele are identical it is called homozygous ,if
the alleles differ it is called heterozygous

Centromere
Middle
Off center
If close to the end
At one terminal end
tip
Name
Metacentric
Sub metacentric
Acrocentric(in this
the short knob like
on the short arm is
called satellite
Telocentric

Group chromosome description
A 1-3 Largest ;1&3 mc,2sc
B 4-5 Large ;sc
C 6-12 &X Medium size;sc
D 13-15 Medium size;ac with satellites
E 16-18 Small ;16 mc,17&18 sc
F 19-20 Small;sc
G 21-22 &Y Small;ac

Modes of inheritance
 Population genetics deals with the study of mode of
inheritance of traits and distribution of genes in
populations.
 A trait is a particular aspect or characteristic of the
phenotype.
 A trait can be-
 Monogenic
 Polygenic/ multifactorial

 All human beings normally have 22 homologous
pairs of chromosomes called autosomes that are
numbered by size and other characteristics.
 Also , one pair of sex chromosomes may be
homologous (X, X) in females or only partly
homologous (X, Y) in males.
 Genes at the same locus on a pair of homologous
chromosomes are alleles.

 When both members of a pair of alleles are
identical, the individual is homozygous for
that locus.
 When the two alleles at a specific locus are
different, the individual is heterozygous for
that locus.

 Exception to this- gametes contain only
single representative of each pair of
chromosomes.
 When 2 gametes join at fertilization- new
individual with paired genes, one from father
& other from mother is formed.

Monogenic Traits
 Traits that develop because of the influence
of a single gene locus are monogenic.
 Also called as mendelian traits.
 Eg-blood group/hemophilia
 Also called as-discrete or qualitative
(yes or no)
 If they are present, these traits still may be
variable and quantifiable in some cases.

Autosomal dominant traits and
penetrance
 If having only one particular allele of the two alleles
on a homologous pair of autosomes (heterozygosity)
is sufficient to lead to the production of the trait, the
effect is autosomal dominant.
 If production of the trait does not occur with only one
particular allele of the two alleles on an autosome
but does occur when both alleles are the same
(homozygosity), then the effect is autosomal
recessive.

 The trait (phenotype) is dominant or
recessive and not the gene itself.
 The nature of the traits is studied by
constructing family trees called pedigrees in
which males are denoted by squares and
females by circles, noting who in the family
has the trait and who does not.

 The study of multiple families will yield the following
criteria for autosomal dominant inheritance:
(1) The trait occurs in successive generations that is, it
shows vertical inheritance
(2) On the average, 50% of the offspring of each parent
who has the trait also will have the trait

(3) if an individual has the gene that results in the trait,
each child has a 50% chance of inheriting the gene
that leads to the expression of the trait
(4) males and females are equally likely to have the
trait
(5) parents who do not have the trait have offspring
who do not have the trait.

 Exceptions to this will be seen in-
 Trait showing nonpenetrance in a particular
offspring.
 A new mutation occurred in the sperm or egg that
formed the offspring.
 Germinal mosaicism occurred, in which case one of
the parents is mosaic in the germ cell line and the
sperm or eggs are of two types-one cell line with and
one cell line without the mutation.

Penetrance
 When a person with a given genotype fails
to demonstrate the trait characteristic for the
genotype, the trait is said to show
nonpenetrance in that individual .
 Incomplete penetrance in any group of
individuals who have the genotype.

Variable expressivity
 In each individual the trait is present or not
when discussing penetrance, if the trait is
present, it may vary in its severity or
expression.
 Thus not all individuals with the trait may
have it to the same extent and may express
varying degrees of effect or severity.

 For example, osteogenesis imperfecta involving type
I collagen
 abnormalities.
(1) multiple fractures
(2) blue sclera
(3) dentinogenesis imperfecta
(4) hearing loss.
 Variation occurs among the different clinical types of
osteogenesis imperfecta

Autosomal recessive traits
 If production of the trait does not occur with only one
particular allele of the two alleles on an autosome
but does occur when both alleles are the same
(homozygosity), then the effect is autosomal
recessive.
 The concept of a gene carrier is used with autosomal
recessive traits.
 The carrier is heterozygous for a recessive gene that
has only subtle, if any, expression of that single
gene.

 Parents of a child with the autosomal
recessive trait are typically heterozygous
(carriers) and most often are diagnosed as
normal.

 In autosomal recessive traits, the following
three gene pairs are found:
 AA-homozygous, not showing the trait or
being a carrier for the trait.
 Aa-heterozygous, not showing the trait but
being a carrier of the trait
 aa-homozygous, showing the trait.

X-linked traits and Iyonization
 Most of the genes on the X and Y chromosomes are
not homologous and are unequally distributed to
males and females.
 Males are hemizygous for X-linked genes, meaning
that they have only half (or one each) of the X-linked
genes.
 Because females have two X chromosomes, they
may be homozygous or heterozygous for X-linked
genes, just as with autosomal genes.

 A normally functioning homologous allele is not
present on another chromosome, recessive genes
on the one male X chromosome express themselves
phenotypically as if they were dominant genes.
 However, X-linked recessive genes must be present
at the same (homologous) locus in females to
express themselves fully.

 Full expression of rare X-linked recessive
phenotypes is almost completely restricted to
males, and occasionally it is seen in females.
 Variable expression in females is because of
a process called LYONISATION.

 The lyonization process starts early in
development when each cell in the female
inactivates almost all of the genes on one of
her two X chromosomes.
 The homologous X chromosome in each
succeeding cell also will inactivate the same
X chromosomes of the pair.

Lyon hypothesis
 In the female all or most of one X chromosome is
genetically inactive and forms Barr body.
 Decision whether maternally derived Xm or
paternally derived Xp is inactive is made early in
embryonic life and is random for each cell.
 All cells subsequently have the same inactive X
chromosome-Xm or Xp.

 There are phenotypes that "run in families" but do not
adhere to patterns of mendelian inheritance.
 These are referred to as complex or common
diseases.
 They have greater incidence compared with
monogenic phenotypes.
 These are the traits influenced by polygenic factors.
Multifactorial inheritance-

 Multifactorial inheritance- trait is determined
by the interaction of a number of genes at
different loci, each with a small but additive
effect, together with environmental factors.
 Many congenital malformations are inherited
as multifactorial traits & categorized as-
continuous or discontinuous.

 multifactorial =polygenic + environmental
 A change in phenotype depends on the result of the
genetic and environmental factors present at a given
time.
 Thus compared with monogenic traits, polygenic
traits are more amenable to change following
environmental (treatment) modification.

 Examples of polygenic traits include height
and intelligence quotient, both of which are
continuous traits greatly influenced by
genetic factors.
 However, height and intelligence quotient
also can be affected greatly by
environmental factors, particularly if they are
deleterious.

Discontinuous multifactorial traits
 This describes the traits determined by
multiple gene loci which are present or
absent depending on the number or nature of
the genetic and/or environmental factors
acting.
 When present these traits can vary
continuously.

 The accepted explanation of discontinuous
multifactorial variation rests on the
assumption that 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.

 The parents of a cleft lip and palate patient
are often unaffected, and there may be no
family history of cleft lip and palate, but
producing an affected child the parents are
deemed to have some underactive genes for
cleft lip and palate formation.

 The parents must have sufficient normally
active genes to have normally formed lips
and palates. Only when the balance exceeds
certain threshold will the malformation
occur, and the further the threshold is
exceeded, the greater the extent of the
malformation

 Liability curve shifts to right for first degree
relatives.
 More severe the malformation- liability curve
shifts to right.
 5% of first degree relatives are affected if the
clefting is bilateral ,whereas only 2% are
affected if unilateral and incomplete.

 Some multifactorial traits show an unequal sex ratio.
 Incidence is increased in the relatives of affected
females.
 This indicates that for this malformation the female
threshold is higher than the male threshold.

Continuous multifactorial traits
 Many normal human characteristics are
determined as continuous multifactorial traits.
These traits by definition have a continuously
graded distribution.
 The majority of individuals are centered
around the mean. Such distribution is
characteristic of a continuous multifactorial
trait.

 For example - height.
- malocclusion
Not an abnormality or disease but a variation of
occlusion in a continuous multifactorial trait.

Etiologic heterogeneity
 Both continuous &discontinuous variation have a
multifactorial basis so that different patients are not
necessarily affected for same reason
 Cleft palate patients no single cause can be
identified ,it can be due to chromosomal disorder –
Wolf Hirschhorn syndrome, trisomy 13 (patau
syndrome),in monogenic disorders such as Vander
Woude syndrome ,it may also be associated with
cigarette smoking ,alcohol , drugs.

Twin studies
 Twin studies are useful in study of population
genetics.
 To determine the role of genetic and
environmental factors.(nature vs nurture)
 Twins can be dizygotic or monozygotic

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

Various methods have been used to differentiate
 Hair&eye color
 Ear form
 Teeth morphology
 Phenylthiocarbamide taste sensitivity
 Blood groups
 Serum proteins (gamma globulins)
 Dermatoglyphics

Concordance & Discordance
 Twins are concordant if they both 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.
 For discontinuous multifactorial traits with both
genetic and environmental contributions, the rate in
monozygotic twins, although less than 100%, will
exceed the rate in dizygotic twins.

 In cleft studies, the monozygotic twin concordance
rate for cleft lip and palate and cleft palate is 35 and
26 per cent, respectively. And for dizygotic twins 5
and 6 per cent, respectively. (Connor and Ferguson-
Smith. 1993).
 This reflects the heritability of the condition,higher
the monozygotic concordance more the genetic
contribution.

Twin studies for occlusal & dentofacial
structures
• Lundstorm (1948)-concluded that genetic factors
have greater influence on craniofacial structures.
• Lundstorm (1955)-genetic factors have greater
influence on sagittal apical base relationship
• Krause Wise&Frei (1959)-concluded that
morphology of craniofacial bones are under strong
genetic influence

• Krupanidhi &V.Surendra Shetty(1989)-assessed
amount of genetic &environmental influence on
dental measurements in twins
 Statistically insignificant intrapair difference in MZ
twins in 11 out of 13 parameters(PMBAW,PMD,basal
arch width,tooth material,arch perimeter,intercanine
width,overjet,overbite,curve of spee, III rugae position &midline)
 Intermolar width & palatal depth showed significant
difference.
 significant difference in DZ twins for 5 parameters -
premolar diameter, upper tooth material, intercanine width; lower
intermolar width, overbite and curve of spee
 may be due to different genetic material.www.indiandentalacademy.com

 Ferguson –Smith(1993) cleft study ,the
monozygotic twin concordance rate for CLP&
CP was 35 &26 % respectively dizygotic twins
5& 6 % respectively

Mutations
A mutation is defined as an alteration or
change in genetic material .
Mutations are due to
 Mutagenic factors –radiation,chemicals etc.
 Spontaneous errors in DNA replication
&repair.

 main groups of chemicals which,cause mutation are-
 Base analogues which mimic standard bases, but
pair improperly (e.g. 5-bromouracil)
 Alkylating agents which add alkyl groups to bases
and hamper correct pairing (e.g. nitrogen mustard or
ethyl methane sulphonate)
 Intercalating agents which intercalate with DNA and
distort its structure (e.g. deamination by
hydroxylamine). www.indiandentalacademy.com

 Mutations can be coded or noncoded .
 Coded are the once that are transmitted.
 Mutations of the somatic cells cannot be
transmitted ,if it occurs in gamete cells it can
be transmitted.
 Mutations can be further divided into -
 length mutations & point mutations.

 In a point mutation a single nucleotide base
is replaced by a different nucleotide base.
 transition –purine to purine
pyrimidine to pyrimidine
 transversion – purine to pyrimidine or vice
versa

 Synonyms –mutations does not alter the
polypeptide product of gene also called
silent.
 Non synonymous –mutations lead to
alterations in the encoded polypeptide

 Missense –a simple base pair substitution
can result in coding for a different amimoacid
and synthesis of altered protein.
 Nonsense –a substitution that leads to the
generation of out of stop codon which will
result in premature termination of translation
of polypeptide chain.

Deletion/insertion
 Deletion is the loss of 1 or more nucleotides
 Insertion is the addition of 1 or more
nucleotides
 results in FRAME SHIFT mutation if these
are not in a multiple of 3

 The majority of mutations are likely to cause reduced
fitness ,a reduced ability of the resulting zygote to
contribute progeny to next generation ,in this way
harmful genes tend be eliminated from the
population
 A balance between the production of
disadvantageous alleles through mutation &their
elimination by selection results in the presence of
harmful alleles in the population at a low frequency

Chromosomal aberrations
 Alterations of the genetic material which
involves many genes & large amount of DNA
1. Numerical aberrations
2. Structural aberrations

1. Numerical aberrations
 Euploidy –triploidy,tetraploidy
 Aneuploidy –monosomies,trisomies
tetrasomies

Structural aberrations
 Translocations –transfer of genetic material from one
chromosome to another
 Inversions –rearrangement within the same chromosome
segment is rotated 180 degrees
 Insertion –one segment is removed from normal position
&inserted in different position
 Deletion –a missing chromosomal segment
 Ring chromosome
 Isochromosome

Chromosome abnormality
 13 trisomy---Patau’s
Mental retardation
Microcephaly
Cleft lip/palate
Micrognathia,small eyes
 18 trisomy--- Edward’s
Mental retardation
Brachycephaly
Micrognathia
Hypodontia
CLP

 XO ---Turners
Retarded growth
Micrognathia
Spade like chest
Ovarian agenesis
 21 trisomy --Down’s
Brachycephaly
Mental retardation
Max hypoplasia
Flat nasal bridge
Delayed eruption
Growth retardation
macroglossia

 XXY--Klinefelter’s
Gynecomastia
Small testes
Decreased facial hair
 4p- Wolf-hirchhorn
Mental retardation
Abnormal facies
CLP
 5p- Cri –du-chat
Mental retardation
Microcephaly
Characterstic cry www.indiandentalacademy.com

Role of neural crest cells
 To understand genetic mechanisms
involved in craniofacial morphogenesis at
the molecular level in the embryo assists –
 To know the role of genetics
1. The etiology of craniofacial abnormalities
2. Regulation of maxillary, mandibular, and tooth
morphology.

 Facial development in the embryo is demarcated by
the appearance of the pre-chordal plate (the cranial
end of the embryo) on the fourteenth day of
development.
 Facial mesenchyme arises from neural crest cells.
 These cells disrupt the ectodermal mesodermal
junction and migrate into the underlying tissue as
ectomesenchymal cells.

 During their migration they undergo a number of
interactions with the extra-cellular matrix, and with
adjacent epithelia to determine the ,nature and
patterning of the neural, skeletal and connective
tissue structures they will form.
 Among the derivatives of the cephalic neural crest
cells arc the maxilla, mandible, zygomatic, nasal
bones, and bones of the cranial vault.

 Neural crest cell migration and the factors that cause these
cells to localise in particular regions is not yet completely
understood.
 Their migration into the branchial arches occurs in a highly
regulated manner.
 This process is presumed to be under the control of genes
known as homeobox genes which endow
neural crest cells with a positional identity, which
mediates aspects of craniofacial morphogenesis and patterning.

The role of cell adhesion molecules
 cell adhesion molecules such as cadherins,
integrins, immunoglobulins, and proteoglycans are
glycoproteins on the external surface of the cell
membranes, and are thought to be important in
embryogenesis, particularly organ formation.
 In craniofacial development the precise positioning
of the neural crest cells in the branchial arches may
involve changes in expression of cell adhesion
molecules.
 They are expressed and down regulated in neural
crest cells during their migratory stages.www.indiandentalacademy.com

Homeobox genes
 Homeobox genes are genes which are highly
conserved through out evolution of diverse
organisms and are now known to play a role in
patterning the embryonic development .
 These can be regarded as master genes of head &
face controlling patterning, induction ,programmed
cell death &epithelial mesenchymal interaction
during development of the craniofacial complex .

Genes of particular interest in craniofacial
developmemt are:
 Hox group
 Msx 1&Msx 2(muscle segment)
 Dlx (distalless)
 Otx (orthodontical)
 Gsc (goosecoid)
 Shh (sonic hedgehog)

Proteins encoded by these homeobox genes are
transcription factors which control transcription of
RNA from the DNA template within cell nucleus.
 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

 These regulatory molecules in the mesenchyme
such as
 fibroblast growth factor (FGF)
 epidermal growth factor (EGF)
 transforming growth factor alpha (TGFa)
 transforming growth factor beta (TGFb)
 bone morphogenetic proteins (BMPs)
 are the vehicles through which homeobox gene
information is expressed in the co-ordination of cell
migration and subsequent cell interactions that
regulate growth.

 By this means different parts of the DNA are
activated in different cells regulating the different
proteins ,enzymes .etc
 These mechanisms hold a key to understand
disease, dysmorphology & are subject of intensive
research in craniofacial biology

Molecular genetics in oral and craniofacial
dysmorphology
 Mutations in fibroblast growth factor- affect suture
development
 Apert, Crouzon and Pfeiffer syndromes
 Mutations in two transcription factors MSX2 and
TWIST
 Boston type craniosynostosis and Saethre-
Chotzen syndrome

 mutation of core binding factor I gene:
Cleidocranial dysplasia
 mutation of long arm of chromosome 5
Treacher Collins syndrome

Molecular genetics in dental development
 Role in epithelial and mesenchymal
interaction
 Bone morphogenetic proteins-2,4 & 7
 FGF 1 & 8 via downstream factors MSX 1 and PAX 9

Control of tooth development
 Muscle specific homeobox genes Msx-l and Msx-2 are
involved in epithelial and mesenchymal interactions.
 Implicated in craniofacial development ie
initiation,developmental position and further development
of tooth buds
 Msx 1 & Pax 9 have been implicated in non syndromic
tooth agenesis
 EDAI and NEMO syndromes that include tooth agenesis.

Disorders of tooth development
 Amelogenesis imperfecta
 It is a group of genetically heterogeneous disorders
affecting enamel formation
 Hypoplastic, Hypocalcified, &Hypomaturation forms
have been described (Witkop 1988)
 It exhibits autosomal dominant,autosomal recessive
& X-linked inheritance
 In humans two amelogens ,AMGX & AMGY have
been cloned &mapped to X & Y chromosomes

 In 1997 MacDoughall et al mapped the ameloblastin
gene within critical region for autosomal dominant AI
at chromosome 4q21 .
 Mutations of several genes may be involved in the
etiology of various types of amelogenesis imperfecta.

Dentinogenesis imperfecta
 It is autosomal dominant
 Occurs in about 1:8000 live birth
 Presents with brownish discoloration of teeth crowns
,susceptible to rapid attrition ,fragile roots &
obliterated pulp chamber
 One type of DI is coupled with osteogenesis
imperfecta
 Most patients with this type of DI have mutations &
deletions for amino acid substitutions in genes for
type 1 collagen

Hypodontia
 Msx 1 is strongly expressed in dental mesenchyme
throughout the bud ,cap &bell stages of
odontogenesis
 Vastardis et al (1996) demonstrated that a mutation
in Msx 1 caused familial tooth agenesis & genetic
linkage analysis of a family with autosomal dominant
agenesis of 2nd premolar & 3rd molar identified a
locus on chromosome 4p as the site of the Msx 1
gene

 Genetic factors are believed to play a major role in
most of the cases of hypodontia with autosomal
dominant, autosomal recessive, X-linked, and
multifactorial inheritance reported.
 A couple of genes (MSXl and PAX9) involved in
dentition patterning have been found to be involved
in some families with nonsyndromic autosomal
dominant hypodontia although there are many other
candidate genes, including KROX-26.

Peg shaped laterals
 This can be an autosomal dominant trait with
incomplete penetrance and variable expressivity as
evidenced by the phenotype sometimes "skipping"
generations and sometimes being a peg-shaped
lateral instead of agenesis and sometimes involving
one or the other or both sides.
 A polygenic mode of inheritance also has been
proposed.

Ectodermal dysplasia
 Hypohidrotic ectodermal dysplasia is a
heterogeneous disorder with clinically many distinct
types
 It is characterized by triad of –
hypotrichosis
hypohydrosis
hypodontia
 Hypodontia varies from few missing teeth to complete
anodontia
 Kere et al identified the gene for X-linked EDA & it
was found to be expressed in keratinocytes, hair
follicles and sweat glands.

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.
 This heterogeneous condition may include other
midline developmental abnormalities of the brain and
other structures that can be due to mutation in the
sonic hedgehog (SHH) gene, SIX3 gene.

Genetic influence on tooth number
,size,morphology,position,& eruption
 Msx 1 &Msx 2 are responsible for stability in dental
patterning .
 Clinical evidence suggests that congenital absence of
teeth &reduction in tooth size are associated
 A study of children with missing teeth found up to half
of their siblings or parents also had missing teeth .

Supernumerary teeth
 Brook (1974) reported that prevalence of
supernumerary teeth in British school children was
2.1%in permanent dentition with male:female ratio of
2:1 , in Hong Kong the prevalence was around 3 % &
male :female ratio 6.5:1 , most common
supernumerary tooth is the mesiodens ,these are
commonly present in siblings & parents of the
patients , it does not follow simple mendalian pattern

Abnormal tooth shape
 Alvesalo &Portin (1969) provided substantial
evidence supporting the view that missing
,malformed lateral incisors may be the result of
common gene defect ,all of these defects show
familial trends ,female preponderance,&association
with other dental anomalies ,such as other missing
teeth ,ectopic canines ,suggesting a polygenic
etiology

Ectopic maxillary canines
 Peck et al (1994) concluded that palatally ectopic
canines were an inherited trait ,being one of the
anomalies in a complex of genetically related dental
disturbances –supernumerary teeth ,missing teeth ,
transposition ,tooth size reduction,other ectopically
positioned teeth,it seems to be a polygenic trait.
 Candidate genes that are proposed possibly to
influence the occurrence of palatally displaced
canines and hypodontia in developmental fields
include MSXl and PAX9. www.indiandentalacademy.com

Submerged primary molars
 It occurs most commonly in mandibular arch ,there is
a high rate of concordance between the monozygotic
twins ,number of studies provide evidence for
genetically determined primary failure of eruption

Maxillary midline diastema
 Numerous etiologies have been proposed –toothsize
arch length discrepancy ,aberrant labial frenum
attachment ,parafunctional habits, tooth loss ,
periodontal disease, deep bite ,maxillary midline
pathology ,broadbent phenomenon ,Gardinger stated
that parents &offsprings appear to share dental
phenotype ,a few authors found heredity to play a
greater role in MMD

 Class II div 1 malocclusion –study done by Harris
(1975) show a higher correlation coefficient between
patient & his immediate family than data from random
pairings of unrelated siblings,thus supporting the
concept of polygenic inheritance

 Class II div 2 malocclusion –it is a distinct clinical
entity & is a more consistent collection of definable
morphometric features occurring simultaneously i.e.
a syndrome ,this often occurs in a combination with
some dental features like poorly developed cingulum
on upper incisors & characteristic crown root
angulation ,teeth thinner in labio lingual dimension,a
further feature is fowardly rotating mandibular
development ,which contributes to deep bite ,chin
prominence &reduced lower face height

 In study done on twins ,there was 100% concordance
for class II div 2 among monozygotic twins &90 %
dizygotic twins were discordant
 Studies point to probably autosomal dominant with
incomplete penetrance &variable expressivity

 Class III malocclusion-the most famous example of
a genetic trait in humans passing through several
generations is the pedigree of the so called –
Hapsburg jaw ,this was famous mandibular
prognathism demonstrated by several generations of
Hungarian/Austrian monarchy

 Strohmayer (1937) did a detail pedigree analysis &
found out that it was a autosomal dominant
trait,other studies found out it to be polygenic trait
 a variety of environmental factors are considered in
its etiology,enlarged tonsils,nasal
blockage,congenital anatomic
defects,endocrine,posture,trauma/disease

ENVIRONMENTAL AND GENETIC INFLUENCES ON
BILATERAL SYMMETRY
 Three types of asymmetry:
 Directional
 Antisymmetry
 Fluctuating asymmetry.

 Directional asymmetry occurs when development of
one side is different from that of the other during
normal development.
 The human lung having three lobes on the right side
and two lobes on the left side
 This may be predicted before development occurs, it
is under significant genetic influence.

 Antisymmetry occurs when one side is larger than
the other, but which side is larger is variable in
normal development and cannot be predicted before
development
 Antisymmetry is much less common than directional
asymmetry.
 These two types of asymmetry are considered
developmentally normal.
 Like directional asymmetry, antisymmetry has a
significant genetic component that is not fully
understood.

 The third type of asymmetry, fluctuating, occurs
when a difference exists between right and left sides,
with which side is larger being random.
 This reflects the inability of the individual to develop
identical, bilaterally homologous structures.

 Fluctuating asymmetry has been observed in the
primary and permanent dentitions.
 The greater amount of fluctuating asymmetry for the
distance between cusps on each tooth than for the
overall crown size of primary second molars and
permanent first molars indicates that the occlusal
morphology of these teeth is influenced more by
environmental factors than the overall crown size.

GENETIC FACTORS AND EXTERNAL
APICAL ROOT RESORPTION
 The degree and severity of external apical root
resorption associated with orthodontic treatment is
multifactorial, involving host and environmental
factors.
 Genetic variation accounts for 50% to 64% of the
variation in EARR of the maxillary incisors.

 Variation in the interleukin-lb gene (IL-l B) in
orthodontically treated individuals accounts for 15%
of the variation in EARR.
 Persons in the orthodontically treated sample who
were homozygous for IL-1B allele "1" were estimated
to be 5.6 times more likely to experience EARR of 2
mm or more than those who were heterozygous or
homozygous for allele "2“(Hartsfield and Everett AJO
2003)

Role of epigenetic factors
 Etiology of malocclusion
genetic environmental
 More important is to understand the interaction.
 The form & size of teeth is principally determined by
genetic factors , but growth and final morphology of
the dentofacial structures is also influenced by
environmental factors.

 The influence of genetics on dentofacial
morphology does not imply that genetic
information is solely located in bones ,but
also in neurological ,muscular &
neuromuscular fields which have influence
on skeleton.

 Mastication ,speech ,facial expression & swallowing
are examples of neuromuscular patterns .
 Although they are under conscious control ,there is
no basis to suggest that these patterns can be
changed permanently.

 Although the bones are also influenced by functional
matrix, the functional matrix comprises of
neuromuscular activity which is influenced by
genetics as well as environmental factors .
 This will have a direct bearing upon the extent to
which a particular malocclusion can be influenced by
therapeutic environmental intervention.
 Salzman (1972) highlighted the familial nature of
tongue thrusting,jaw posturing, & orofacial soft tissue
mannerism .

Human genome project
 Begun formally in 1990, the U.S. Human Genome
Project is a 13-year effort coordinated by the U.S.
Department of Energy and the National Institutes of
Health.

 Determine the sequences of the 3 billion chemical
base pairs that make up human DNA.
 identify all the approximate 30,000 genes in human
DNA.
 Locate genes to specific chromosomes.
 Identify near neighbours of genes.
 store this information in databases.
 Determination of gene defects.
 Various linkage analysis.
Project goals

The Oral &Craniofacial genome project seeks to set up
collaborative laboratory research projects on human
&mouse embryonic tissue
The objective is to build up DNA libraries with a view to
discover the genes for normal & abnormal oral &
craniofacial development .

Conclusion
 Contrary to the presumption that malocclusions of
"genetic cause" are less amenable to treatment than
those of an "environmental cause," a change in
environmental factors can affect a polygenic trait
with a high estimate of heritability.
 The effect depends on the response of the patient to
the change in environment (e.g., treatment).

 In the future, orthodontists ability to treat
patients better will depend on investigations
into how environmental factors affect gene
expression that influences malocclusion.

We used to think that our fate is in stars
Now we know that in large measure it is in our
GENES.
For more details please visit

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