This doc is related to oral medicine and radiology

1. Genetic
Approaches in the
Study of Oral
Disorders
- DR. JAGDISH ZADKE

2. General Learning Objective
To understand the different genetic approaches used in the
study of oral disorders
2
Specific Learning Objective
1. To know the definition, history and a brief overview of genetics
2. To know the basic genetic principles
3. To understand the genetic basis of diseases
4. To know the mendelian and chromosomal disorders in oral health
5. To know the genetic basis of common oral health diseases
6. To understand genetic epidemiology
7. To know the role of genetics in preventive and social measure

3. Genetics
Definition, History, Overview
3

4. Definition
Genetics is the study of heritable biological
variation
4

5. Landmarks in the History of Genetics
Source: http://cogweb.ucla.edu/ep/DNA_history.html
1859
Darwin
publishes The
Origin of Species
1865
Gregory Mendel
publishes evidence for
the discreteness and
combinatorial rules of
inherited traits
1869
Miescher
discovers "nuclein"
(DNA) in the cells from
pus in open wounds
1926
Muller
formulates the chief
principles of
spontaneous gene
mutation
1944
Oswald Avery
identifies nucleic acids
as the active principle in
bacterial transformation
1950
Erwin Chargaff
shows that the four
nucleotides are not
present in nucleic acids
in stable proportions
1952
Hershey & Chase
show that on infection of the host
bacterium by a virus, at least
80% of the viral DNA enters the
cell and at least 80% of the viral
protein remains outside.
1953
Watson & Crick
determine that
deoxyribonucleic acid
(DNA) is a double-strand
helix of nucleotides.
1970
King & Wilson
Comparisons between
chimpanzee and human
genomes finds that they
diverge by only 1.6%
1980
McClintock
The genome may be
controlling aspects
of its own mutation
1984
McGinnis
discovers homeotic
(Hox) regulatory genes,
responsible for the basic
body plan of most
animals.
2000
Human Genome
Project
An accurate
chemical map of
the genome
Traits are carried
by discrete units, or
genes; the results
are not appreciated
until 1900
The gene
constitutes the
basis of life and
evolution by virtue
of its property of
reproducing its own
internal changes
DNA replication is
possible through
the complementary
nature of the two
strands
Revealed that a human
being contains 20,000 to
25,000 genes within the
nucleus of each somatic
cell and another nine genes
that are encoded within the
mitochondria found in all
human cells.

6. Overview of DNA and
Gene
6

7. Basic Genetic Principles
7

8. 8
➝ Every cell in the human body contains 23 pairs of
chromosomes with one chromosome in the pair inherited
from each parent.
➝ Each chromosome, in turn, contains thousands of DNA
gene sequences, some of which are active or expressed
and others that are dormant.
➝ Factors like time, the environment and the type of cell
containing the chromosome (e.g., tooth, brain, kidney,
etc.), determine whether or not the gene will be
expressed.
➝ The control of gene expression is essential for the proper
BASIC GENETIC PRINCIPLES

9. 9
Genetic
Disorders
Mendelian
Inheritance
Autosomal
Dominant
Autosomal
Recessive
Sex Linked
Chromosomal
Anomalies
Multifactorial
Inheritance

10. 10
• Only one mutated gene necessary
• Affected person has usually one affected parent
• 50% chance of inheritance
• Eg: Dentinogenesis Imperfecta and Marfan Syndrome
Autosomal
dominant
• Two copies of mutated gene necessary
• Usually have unaffected parents both carrying single copy
of mutated gene
• 25% chance of inheritance
• Eg: Cystic Fibrosis and some forms of ED and AI
Autosomal
recessive
• Mutation presen on either X or Y chromosome
• 50% chance of inheritance for son if gotten from mother
• Daughter could be a carrier if gene transmitted
• Eg: X;linked hypophosphatemic rickets, Hemophilia
Sex Linked
Mendelian Inheritance

11. 11
➝ Some disorders result from defects in chromosomes that
involve multiple genes.
➝ This includes duplication of all or part of a chromosome,
deletion of part of a chromosome or translocation of one
chromosome onto another.
➝ Since chromosomal anomalies affect many genes, they
result in multiple physical defects as well as intellectual and
developmental disturbances.
➝ Down syndrome (trisomy 21) is one example of a disorder
with a chromosomal anomaly.
➝ Individuals with chromosomal anomalies may have dental
and/or craniofacial anomalies related to the genetic
modification.
CHROMOSOMAL ANOMALIES

12. 12
➝ Many common diseases are not inherited as a single gene
defect but instead are the result of modifications in gene
expression or as gene-environment interactions.
➝ This includes diseases such as diabetes, hypertension,
and bipolar disorder, non-syndromic cleft lip and/or palate,
dental caries, and periodontal disease.
➝ These diseases are considered “complex” because they
involve multiple interactions between genes and
environmental factors such as smoking, diet, stress, and
environmental chemicals.
➝ An individual’s response to environmental factors and his
or her subsequent susceptibility to disease is related to
mechanisms that modify gene expression without altering
the DNA sequence.
MULTIFACTORIAL INHERITANCE

13. 13
➝ Many common diseases are not inherited as a single gene
defect but instead are the result of modifications in gene
expression or as gene-environment interactions.
➝ This includes diseases such as diabetes, hypertension,
and bipolar disorder, non-syndromic cleft lip and/or palate,
dental caries, and periodontal disease.
➝ These diseases are considered “complex” because they
involve multiple interactions between genes and
environmental factors such as smoking, diet, stress, and
environmental chemicals.
➝ An individual’s response to environmental factors and his
or her subsequent susceptibility to disease is related to
mechanisms that modify gene expression without altering
the DNA sequence.
MULTIFACTORIAL INHERITANCE

14. Genetic Basis For
Disease
14

15. SINGLE NUCLEOTIDE
POLYMORPHISM
15
➝ Within each individual’s genome are sequence variations
(single nucleotide polymorphisms or SNPs) that may be
associated with a complex disease, but are not considered
causative.
➝ SNPs (pronounced “snips”) are the most frequent form of
human genetic variation.
➝ They occur approximately every 1,000 nucleotides in the
human genome.
➝ Because only about 3 to 5 percent of a person’s DNA
sequence codes for the production of proteins, most SNPs
are found outside of “coding sequences” and are thought
not to have a functional effect on a person’s health.
➝ SNPs found within a coding sequence are of particular
interest to researchers as they are more likely to alter the
biological function of a protein.

16. SINGLE NUCLEOTIDE
POLYMORPHISM
16
➝ Although most SNPs do not produce physical changes in people,
scientists believe that some SNPs that occur in certain genes may
predispose a person to disease by altering the function of the
gene product.
➝ SNPs can also influence how a person responds to a particular
drug regimen.
➝ SNP variation provides the highest-resolution genomic fingerprint
for tracking disease genes.
➝ These sequence variations have been identified as part of the
sequencing of the entire human genome and have been
incorporated into studies referred to as genome-wide association
studies (GWAS).
➝ In these studies, individuals with a certain disease, like dental
caries, are compared to individuals without the disease by looking
at the SNP sequences at millions of sites throughout the genome.

17. SINGLE NUCLEOTIDE
POLYMORPHISM
17
➝ Using sophisticated, statistical analysis, researchers
identify specific SNPs that are more frequently associated
with the disease.
➝ Once a site on the genome is identified as a potential site
of the gene in question, further investigation is completed
to identify genes involved and understand their clinical
significance.
➝ Studies of complex disorders, by definition, include relevant
environmental factors that are known to contribute to the
disease.
➝ For example, a GWAS study of dental caries would need to
include fluoride exposure, socioeconomic status, dietary
habits, oral microflora, and oral hygiene habits to be able to
assess the gene-environment interactions that contribute to
disease.

18. 18

19. Gene Identification
19

20. GENE IDENTIFICATION
20
➝ In the case of simple genetic conditions, when disease
causing mutations are identified, genetic information often
permit diagnostic testing and family counseling.
➝ Genetic testing can confirm clinical diagnoses, provide
information to predict prognosis, and in some cases help
clinicians select the most appropriate treatment.
➝ Genetic testing for complex diseases is more problematic
at this time.
➝ With current technologies it is possible to identify genetic
variation (polymorphisms) at targeted genomic sites in
specific individuals.

21. GENE IDENTIFICATION
21
➝ While this may be considered “genetic testing,” the clinical
validity and utility such a test provides, particularly for the
clinical care of an individual, must be demonstrated.
➝ The utility of genetic information to predict disease risk is
predicated on the identification of genetic polymorphisms
that are, in fact, associated with disease risk in a
meaningful way.
➝ In contrast to the direct relationship between genetic
mutations and the occurrence of symptoms in simple
genetic diseases, the relationship between genetic
polymorphisms and the occurrence of symptoms in
complex diseases is much more difficult to validate.

22. GENE IDENTIFICATION
22
Gene reported to be
etiologically important in
disease
Characterise gene
variants
Gene testing
Mendelian/Chromosomal
Conditions
Diagnostics
Treatment intervention Prognostic indicator Counseling relatives
Complex Genetic
Disease
Susceptibility
Clinical implications and
applications unclear

23. Mendelian/
Chromosomal Disorders
in Oral Health
23

24. GENES INVOLVED IN TOOTH
DEVELOPMENT
➝ Initiation, morphogenesis, and differentiation are the three
fundamental processes involved in organogenesis.
⇾ A group of cells interpret positional information
provided by other cells to initiate organ formation
both at the right place and time (initiation).
⇾ This leads to the formation of an organ rudiment
(morphogenesis),
⇾ This is followed by the development of organ −
specific structures (differentiation)
24

25. GENES INVOLVED IN TOOTH
DEVELOPMENT
➝ Development of teeth is under strict genetic control.
➝ More than 300 genes are involved in determination of the
position, number, and shape of different types of teeth.
➝ Mutations in those genes encoding transcription factors
and signaling molecules involved in odontogenesis is
responsible for numerous abnormalities of the teeth.
➝ Most commonly studied genes in tooth development are
homeobox genes.
25

26. Homeobox Genes
➝ A homeobox (HOX) is a DNA sequence of about 180
basepairs long, found within genes that are involved in the
regulation of development (morphogenesis) of animals,
fungi, and plants.
➝ Genes that have a homeobox are called homeobox genes
and form a homeobox gene family.
➝ Homeobox genes encode transcription factors, which
typically switch on cascades of other genes.
➝ HOX genes are a particular cluster of homeobox genes
which function in patterning the body axis thereby providing
the identity of particular body region and they determine
where body segments grow in a developing fetus.
26

27. Homeobox Genes
➝ Mutations in any one of these genes can lead to the growth
of extra, typically non-functional body parts.
➝ Thus, mutations to homeobox genes can produce easily
visible phenotypic changes.
➝ Humans generally contain homeobox genes in four
clusters,
27
HOXA • Chromo
2
HOXB • Chromo
7
HOXC • Chromo
12
HOXD • Chromo
17

28. Homeobox Genes
➝ HOX gene network appears to be active in human tooth
germs between 18 and 24 weeks of development.
➝ The important members of the homeobox genes involved
in tooth development.
28
PAX MSX DLX
LHX BARX RUNX-2

29. PAX 9
➝ They are important regulators of organogenesis that can
trigger cellular differentiation.
➝ PAX-9 is widely expressed in the neural crest derived
mesenchyme involved in craniofacial and tooth
development.
➝ PAX-9 gene is mapped onto 14q12-q13 and mutations in
this gene can lead to non-syndromic tooth agenesis.
➝ PAX-9-/- mice show cleft of secondary palate besides other
skeletal alterations, lack thymus and parathyroid glands,
and show absence of teeth.
➝ Tooth development in homozygous PAX-deficient mouse
embryos is arrested at the bud stage, indicating that PAX-9
is required for tooth development to proceed beyond this
stage.
➝ PAX-9 is required for the mesenchymal expression of Bmp-
29

30. MSX-1
➝ The MSX gene is a member of MSX homeobox gene family, a
small family of homeobox genes related to the drosophila gene
muscle segment homeobox (msh).
➝ At present, two human MSX genes-MSX-1 and MSX-2, have
been isolated. MSX-1 gene is mapped onto 4p16.1.
➝ MSX-1 and MSX-2 are found to be expressed in several
embryonic structures including pre-migratory and migratory
neural crest cells, as well as in the neural crest derived
mesenchyme of the pharyngeal arches and median nasal
process.
➝ The expression of this gene is observed very early in the
odontogenic mesenchyme.
➝ They are expressed in undifferentiated multipotential cells that
are proliferating or dying and they provide positional information,
and regulate epithelial-mesenchymal signalling in cranio-facial30

31. MSX-1
➝ MSX-1 gene encode a group of homeodomain transcription
factors required in different stages of development, like
patterning, morphogenesis, and histogenesis and they function
as transcriptional repressors.
➝ It has been shown that MSX-1 inhibits cell differentiation by
maintaining high levels of cyclin DI expression and Cdk-4
activity, thus preventing the exit from the cell cycle and enabling
the cells to respond to proliferative factors.
➝ The loss of function mutation would lead these cells to
differentiate earlier and stop proliferating, producing impaired
morphogenesis.
➝ MSX-/- mice have cleft secondary palate, lack all teeth whose
development is arrested at bud stage, and have skull, jaw, and
middle ear defects.
31

32. DLX
➝ DLX (Distal less) family of homeobox genes consists of six
members (DLX 1-6) and is expressed in the epithelium and
mesenchyme of the branchial arches, tooth bud mesenchyme,
dental lamina, cranial neural crest, dorsal neural tube, and
frontonasal process.
➝ Mutation in these genes results in abnormalities affecting first
four branchial arch derivatives including mandible and calvaria.
➝ DLX genes have been involved in the patterning of
ectomesenchyme of the first brachial arch with respect to tooth
development.
➝ Loss of function mutation of these genes apparently resultsin
failure of development of upper molars.
32

33. LHX
➝ Lim homeodomain transcription factors (LHX-1 and LMX1-b) are
expressed in neural crest derived ectomesenchyme of first
branchial arch.
➝ Improper expression of this gene leads to abnormal
development of first arch derivatives including tooth agenesis
and cleft palate.
➝ Recently a Lim homeobox gene, LHX-8, is found to be
expressed in murine embryonic palatal mesenchyme.
➝ Targeted deletion of this gene resulted in a cleft secondary
palate in LHX-8 homozygous mutant embryos.
33

34. BARX
➝ Telencephalon, diencephalon, mesencephalon, hindbrain,
spinalcord, cranial and dorsal root ganglia, craniofacial
structures, and palate are the expression sites for Barx gene.
➝ Improper expression of this gene results in failure of nervous
system to develop and cleft palate formation.
➝ BARX-1 is expressed in the mesenchyme of the mandibular and
maxillary process and in the tooth primordial.
➝ BARX-2 is expressed in the oral epithelium prior to the
➝ tooth development.
34

35. RUNX
➝ RUNX 2 (Runt related protein) is a transcription factor and a key
regulator of osteoblast differentiation and bone formation.
➝ Also, analysis of RUNX-2 showed that it is restricted to dental
mesenchyme between the bud and early bell stages of tooth
development.
➝ Epithelium-mesenchymal recombinants demonstrated that the
dental epithelium regulates mesenchymal RUNX-2 expression
during the bud and cap stages.
35

36. TOOTH AGENESIS
➝ Its prevalence in permanent dentition reaches 20% and its
expressivity ranges from only one tooth, usually a third
molar, to the whole dentition.
36
Tooth
Agenesis
Syndromic
Non
Syndromic

37. NON-SYNDROMIC TOOTH AGENESIS
➝ Isolated, non-syndromic tooth agenesis can be sporadic or
familial and may be inherited as an autosomal dominant,
recessive, or X-linked mode.
➝ Molar oligodontia, second premolar and third molar
hypodontia, incisor-premolar hypodontia exemplify non-
syndromic agenesis.
➝ The genetic cause for Incisor-premolar hypodontia has not
been found yet but mutations in MSX-1, MSX-2, EGF, and
EGFR have been excluded. 37
Molar
Oligodontia
PAX-9 14q12-q13
Premolar
Oligodontia
MSX-1 4p16.1

38. SYNDROMIC TOOTH AGENESIS
➝ Tooth agenesis is associated with many syndromes
because many genes take part in molecular mechanisms
common to tooth and other organs development.
➝ The following are the commonly associated syndromes.
38
Ectodermal
Dysplasia
Wiktop Tooth
and Nail
Syndrome
Reiger
Syndrome

39. ECTODERMAL DYSPLASIA
➝ Ectodermal dysplasias are a group of 192 distinct disorders
that involve anomalies in at least two of the following
ectodermal-derived structures: Hair, skin, nails, and teeth.
➝ The most common EDs
⇾ Hypohidrotic ED (Christ-Siemens-Touraine
syndrome) and
⇾ Hidrotic ED (Clouston syndrome)
39

40. HYPOHIDROTIC ECTODERMAL
DYSPLASIA
➝ This disease is produced by point mutations, deletions, or
translocations in the EDA gene, mapped to Xq12-q13.1.
➝ EDA gene encodes ectodysplasin-A, a 391 amino acid
protein that belongs to the TNF-ligand family.
➝ Ectodysplasin plays a vital role during development by
promoting interaction between ectodermal and
mesodermal layers.
➝ Ectodermal-mesodermal interactions are essential for
many structures derived from ectoderm, including skin,
hair, nails, teeth, and sweat glands.
➝ Mutated EDA gene leads to the production of a non-
functional version of the ectodysplasin, a protein which in
turn cannot trigger the normal signals needed for the
normal ectodermal mesodermal interaction resulting in the
defective formation of the corresponding derivatives. 40

41. HIDROTIC ECTODERMAL DYSPLASIA
➝ Hidrotic ED is an autosomal dominant disorder caused by
mutations in GJB-6, which encodes the gap junction beta
protein connexin 30, a component of intercellular gap
junctions.
➝ Connexon mediates the direction of diffusion of ions and
metabolites between the cytoplasm of adjacent cells.
➝ Mutations in this gene deregulate the trafficking of the
protein and are thus associated with defects like palmar-
plantar hyperkeratosis, generalized alopecia, and nail
defects.
41

42. WIKTOP TOOTH AND NAIL SYNDROME
➝ The tooth-and-nail syndrome (Witkop syndrome) is a rare
autosomal dominant ectodermal dysplasia manifested by
defects of the nail plates of the fingers and toes and
hypodontia with normal hair and sweat gland function.
➝ A nonsense mutation within MSXI homeobox has been
responsible for this disorder.
➝ The protein produced from the mutated allele would be
truncated, and lack the entire C-terminal region that is
important for protein stability and DNA binding.
➝ The mutant protein would have no biological function, and
the haplo insufficiency is probably the pathogenic
mechanism.
42

43. REIGER SYNDROME
➝ This is characterized by hypodontia, malformation of the
anterior chamber of the eyes, and umbilical anomalies.
➝ The maxillary deciduous and permanent incisors and
second maxillary premolars are most commonly missing,
and cleft palate may be present.
➝ The mandibular anterior teeth have usually conical crowns.
➝ Mutations responsible for this malformation have been
found in PITX-2 (paired like homeodomain transcription
factor 1), a gene mapped to 4q25-q26.
➝ PITX-2 is a gene involved in tooth development and is
more restricted to dental lamina.
➝ PITX-2-null mice revealed that PITX-2 was both a positive
regulator of Fgf-8 and a repressor of Bmp-4 signaling
suggesting that PITX-2 may function as a coordinator of
craniofacial signaling pathways.
43

44. STRUCTURAL TEETH DEFECTS
44
Amelogenesis
Imperfecta
Dentinogenesis
Imperfecta

45. AMELOGENESIS IMPERFECTA
➝ Genes that code amelogenin and enamelin are AMELX
and ENAM.
➝ Amelogenin gene is located on X and Y chromosome.
➝ Apart from tooth enamel, amelogenin is found in bone,
bone marrow, and brain cells.
➝ AMELX gene located on X-chromosome has a major role
in enamel formation, whereas AMELY gene located on Y-
chromosome is not needed for enamel formation.
➝ Mutations in the AMELX and ENAM genes are mainly
demonstrated to result in Amelogenesis imperfecta.
45

46. AMELOGENESIS IMPERFECTA
➝ Recently, mutations of two genes encoding enamel
proteases,Kallikrein-4 (KLK-4) and MMP-20
(metalloproteinases), have been reported.
➝ Amelogenesis imperfecta can be inherited as autosomal
dominant, recessive, or as X-linked recessive (Xp-22) trait.
➝ Mutations in AMELX gene cause X-linked AI, whereas
mutations in ENAM gene cause autosomal inherited forms
of AI.
46

47. DENTINOGENESIS IMPERFECTA
➝ Dentin consists of 65% inorganic and 35% organic
substance.
➝ The major portion of the organic substance is made of
Type I collagen, a product of COLIAI and COLIA-2 genes.
➝ This trimeric collagen molecule forms the foundation for
several mineralized tissues including bone and dentin.
➝ There are numerous non-collagenous proteins present in
dentin, some of which interact with collagen to initiate
and/or regulate mineralization.
47

48. DENTINOGENESIS IMPERFECTA
➝ The most abundant non-collagenous protein is dentin
sialophosphoprotein, which is a product of DSPP gene
located on 4q21.3.
➝ Dentin sialophosphoprotein is a highly phosphorylated
protein that attaches to the type 1 collagen fibril and helps
in regulation of mineralization at specific sites within the
collagen.
➝ Mutations in either COL or DSPP genes can alter this
interaction resulting in abnormal mineralization and a
Dentinogenesis imperfecta phenotype
48

49. SYNDROME ASSOCIATED ORO-FACIAL
DEFECTS
49
Van der
Woude
Syndrome
Crouzon
Syndrome
Apert
Syndrome
Treacher
Collins
Syndrome
Down
Syndrome

50. VAN DER WOUDE SYNDROME
➝ Van der Woude syndrome is an autosomal dominant
syndrome typically consisting of a cleft lip or palate and
distinct pits of the lower lip.
➝ Most cases of V-W syndrome are due to deletion in
chromosome 1q32-q41 and recently locus 1p34 is
reported.
➝ IRF-6 gene (interferon regulatory factor) mutations are
responsible for this disorder but the exact mechanism of
this mutation on craniofacialdevelopment is uncertain.
50

51. CROUZON SYNDROME
➝ Crouzon syndrome is characterized by premature closing
of the cranial sutures leading to cranial malformations.
➝ Maxillary hypoplasia and midline maxillary pseudo cleft are
the common oral manifestations.
➝ Mutations in the FGFR-2 gene, located on 10q24, cause
Crouzon syndrome.
➝ The FGFR-2 gene provides instructions for making a
protein called fibroblast growth factor receptor 2.
51

52. CROUZON SYNDROME
➝ This protein plays an important role in bone growth,
particularly during embryo development.
➝ Immature osteoblasts respond to FGF treatment with
increased proliferation, whereas in differentiating cells FGF
does not induce DNA synthesis but causes apoptosis.
➝ Mutations in FGFR-2 gene probably overstimulate
signaling by the FGFR-2 protein, which causes the bones
of the skull to fuse prematurely.
52

53. APERT SYNDROME
➝ Apert syndrome is characterized by premature closing of
the cranial sutures and characteristic limb defects.
➝ Mutations in the FGFR-2 gene (10q25-26) causes Apert
syndrome.
➝ The FGFR-2 gene produces a protein called fibroblast
growth factor receptor 2.
➝ Among its multiple functions, this protein signals immature
cells to become bone cells in a developing embryo and
fetus.
➝ A mutation in a specific part of the FGFR-2 gene alters the
protein and causes prolonged signaling, which can
promote the premature fusion of bones in the skull, hands,
and feet.
53

54. TREACHER COLLINS SYNDROME
➝ Treacher Collins syndrome is characterized by defects of
structures derived from the first and second branchial
arches.
➝ Hypoplastic zygomas and mandible, coloboma, ear
defects, lateral facial clefting, and cleft palate are seen in
these patients.
➝ Mutations in the TCOF-1 (5q32 - q33.1) gene cause
Treacher Collins syndrome.
➝ The TCOF-1 gene provides instructions for making a
protein called treacle.
54

55. TREACHER COLLINS SYNDROME
➝ Treacle plays a key role in pre-ribosomal processing and
ribosomal biogenesis.
➝ In mice, haploinsufficiency of TCOF-I results in a depletion
of neural crest cell precursors through high levels of cell
death in the neuroepithelium, which results in a reduced
number of neural crest cells migrating into the developing
cranio-facial complex leading to the specific problems with
facial development found in Treacher Collins syndrome.
55

56. DOWN SYNDROME
➝ Down syndrome is characterized by single transverse
palmar crease, epicanthic folds, up slanting palpebral
fissures, shorter limbs, hypotonic muscles, learning
disabilities, and physical growth retardation.
➝ Trisomy 21, mosaicism, and translocation are the various
genetic events that result in Down syndrome.
➝ And 95% of Down syndrome results from trisomy 21, 3-4%
of cases from translocation, and 1-2% by mosaicism.
➝ Most cases of Down syndrome result from trisomy 21,
which means each cell in the body has three copies of
chromosome 21 instead of the usual two.
➝ When only few of the body’s cells have an extra copy of
chromosome 21, these cases are called mosaic Down
syndrome.
56

57. DOWN SYNDROME
➝ Although uncommon, Down syndrome can also occur
when part of chromosome 21 becomes attached
(translocated) to another chromosome before or at
conception.
➝ Affected people have two copies of chromosome 21, plus
extra material from chromosome 21 attached to another
chromosome.
➝ These cases are called translocation Down syndrome.
➝ Most cases of Down syndrome are not inherited, but occur
as random events during the formation of reproductive cells
(eggs and sperm).
➝ An error in cell division called nondisjunction results in
reproductive cells with an abnormal number of
chromosomes (trisomy 21).
➝ Mosaic Down syndrome is also not inherited, whereas
57

58. OTHERS
58

59. OTHERS
59

60. Complex Disorders in
Oral Health
60

61. 61
CARIES
➝ A predictive test for dental caries does not currently exist.
➝ Risk Profile: Candidate gene and GWAS studies have
identified a number of potential susceptibility loci. These
include MMP10, MMP14, and MMP16;3 MPPED2 and
ACTN2;4 Tuftelin;5 as well as chromosomal regions with
unknown function (i.e., rs7791001 in 7q22.3).
➝ Potential Clinical Utility: A genetic test for caries
susceptibility has the potential to identify patients at risk
prior to disease occurrence; however, there are currently
no genetic tests with this predictive ability. There may also
be opportunity to develop genetic tests which may lead to
more targeted therapies that precisely address the
individual’s personal risk.

62. 62
CARIES
➝ Significance of the Information (Effect Size): Not
applicable at this time.
➝ Does the Information Change Treatment of the Patient?
Currently the most reliable predictor of caries risk is the
presence of at least one caries lesion. Other clinical risk
indicators include a diet with frequent (e.g., more than
three) exposures per day to simple carbohydrates, poor
oral hygiene, visible plaque, high levels of cariogenic
bacteria, low socioeconomic status and low oral health
literacy, among other things. In the future, genetic
information about an individual’s risk profile may change
how disease is managed.

63. 63
PERIODONTAL DISEASES
➝ Risk Profile: Candidate genes and GWAS studies have
identified a number of loci for study. A recent systematic
review found there was a strong level of evidence that
SNPs in the vitamin D receptor (VDR), FccRIIA and
interleukin-10 (IL10) genes and a moderate level of
evidence for the IL1-alpha and IL1-beta genes.
In addition to genetic testing of the host, genetic testing for
microbial identification may offer an additional avenue to
explore for clinical application.

64. 64
PERIODONTAL DISEASES
➝ Potential Clinical Utility: Identifying a basis for severe
disease in young individuals or as a means to better
understand drivers of inflammation in excess of local
factors; as well as monitoring treatment responses are
among applications of host testing.
➝ Microbial identification may have value when coupled with
antibiotic sensitivity testing for selecting antibiotics.
➝ Patients who have periodontitis that is refractory to
treatment also may benefit from microbial assessments
and monitoring.
➝ In addition, identification of patient genes that confer risk
for microbial imbalance may be an important part of the
puzzle since gene-environment interactions are key when
considering the interaction of the microbiome and the host
at mucosal surfaces.

65. 65
PERIODONTAL DISEASES
➝ In addition, microbial testing may provide insight for patient
management when treatment responses are poor—for
example, under circumstances when there are low plaque
scores, yet paradoxically high bleeding on probing and/or
increased pocketing following exhaustive periodontal
therapy and careful maintenance.
➝ Although it may be possible one day to combine insight
about genetic information, comorbidities (e.g., diabetes),
and environmental factors (e.g., smoking) to enhance
decision making regarding treatment options and
outcomes, this is not yet the state of the art.
Significance of the Information (Effect Size): Not
applicable at this time.

66. 66
PERIODONTAL DISEASES
➝ Does the Information Change Treatment of the
Patient?
➝ At this time, neither genotyping nor microbial testing are
recommended as a routine dental procedure to identify the
presence, absence, or severity of the disease.
➝ Clinical measurements (i.e., probing measurements and
radiographic evaluations) for assessing the presence or
absence of disease remain the single best method for
assessing disease.

67. 67
OTHERS

68. Genetic Epidemiology
68

69. Definition
A science which deals with the etiology,
distribution, and control of disease in groups
of relatives and with inherited causes of
disease in populations.
-Newton Morton
69

70. 70
STEPS IN GENETIC EPIDEMIOLOGY
1. Establishing that there is a genetic component to the
disorder.
2. Establishing the relative size of that genetic effect in relation
to other sources of variation in disease risk (environmental
effects such as intrauterine environment, physical and
chemical effects as well as behavioral and social aspects).
3. Identifying the gene(s) responsible for the genetic
component.
Family
studies
Seggregation Linkage Association
Population
studies
Association

71. 71
METHODS IN GENETIC EPIDEMIOLOGY
1. Genetic risk studies:
• What is the contribution of genetics as opposed to environment
to the trait?
• Requires family-based, twin/adoption or migrant studies.
2. Segregation analyses:
• What does the genetic component look like (oligogenic 'few
genes each with a moderate effect', polygenic 'many genes each
with a small effect', etc)?
• What is the model of transmission of the genetic trait?
• Segregation analysis requires multigeneration family trees
preferably with more than one affected member.

72. 72
METHODS IN GENETIC EPIDEMIOLOGY
3. Linkage studies:
• What is the location of the disease gene(s)?
• Linkage studies screen the whole genome and use parametric or
nonparametric methods such as allele sharing methods {affected
sibling-pairs method} with no assumptions on the mode of
inheritance, penetrance or disease allele frequency (the
parameters). The underlying principle of linkage studies is the
co-segregation of two genes (one of which is the disease locus).
4. Association studies:
• What is the allele associated with the disease susceptibility?
• The principle is the coexistence of the same marker on the same
chromosome in affected individuals (due to linkage
disequilibrium).
• Association studies may be family-based or population-based.
• Most recently, genome-wide association studies (GWAS) have
been the norm for most robust results

73. 73
GENETIC EPIDEMIOLOGIC APPROACH
• When the question is whether a disease has a genetic
component, the detection and estimation of familial aggregation
(e.g., higher occurrence rates in siblings or offspring) is the first
step in the approach.
• This may already be known from descriptive epidemiology
studies. Results of observational studies on siblings, parent-
offspring concordance, twins, adoptees and even migrants may
suggest a genetic component in the etiology of a disease or trait.
• Familial aggregation of a trait is a necessary but not sufficient
condition to infer the importance of genetic susceptibility,
because environmental and cultural influences can also
aggregate in families, leading to family clustering and excess
familial risk.

74. 74
GENETIC EPIDEMIOLOGIC APPROACH
• Similar environment may be the reason for familial aggregation.
• With rising divorce rates, study of recurrence risk in half-siblings
is another powerful method to test for parent-specific events.
• In an application of this method, multiple sclerosis appeared to
have a genetic basis transmitted more from mothers than fathers
• Other traditional designs for distinguishing non-genetic shared
family effects from genetic effects have been studies of twins
and adoptees.

75. 75
TWIN STUDIES
• Twin studies have been traditionally used to estimate the genetic
contribution to a trait through the comparison of monozygotic
(MZ) pairs (who share all their genes) with dizygotic (DZ) twins
(who share half of their genes in common).
• The greater similarity of MZ twins than DZ twins is considered
evidence of genetic factors.
• The usual assumptions of a classic twin study are
1. random mating,
2. no interactions between genes and environment, and
3. equivalent environments for MZ and DZ twins.

76. 76
TWIN STUDIES
• In the study of a complex trait, phenotypic variance is divided into
a
1. component due to inherited genetic factors (heritability),
2. a component due to environmental factors common to both
members of the pair of twins (the shared environmental
component),
3. a component due to environmental factors unique to each twin
(the nonshared environmental component).
• Twin studies have been used to establish the presence of a
genetic component in the etiology in many diseases including
celiac disease, Alzheimer disease, schizophrenia and cancer.

77. 77
ADOPTION STUDIES
• Adoption studies also permit the separation of childhood rearing
effects from genetic effects by studying the similarity of adopted
children with their biological and foster parents.
• The assumptions are that the resemblance between an adopted
child and biological parent is due only to genetic effects, while
that between the adopted child and the adoptive parent is only
environmental in origin.
• However, sometimes the representativeness of adoption studies
can be questioned due to special circumstances surrounding
adoption (adoption bias).
• In contrast, twins are born into all classes of society.

78. 78
• Migration studies also provide clues for genetic vs environmental
causes.
• If the incidence in migrants revert to the host population's
incidence, this suggests stronger environmental factors in
pathogenesis, hypertension, and cancer.
• Once a genetic basis is established, the next step is to define the
mode of inheritance of the trait/disease or to map the specific
gene(s) contributing to the trait.

79. 79
SEGREGATION ANALYSIS
• Helps in defining the mode of inheritance
• Answers questions like
1. Is there a single major gene or are there many genes of
small effect that influence the trait?
2. Could there be two major genes that are interacting to cause
variation in the trait?
• Segregation analysis is most useful in single gene disorders
due to a biallelic gene.
• When multiple loci with multiple alleles are involved as in
most complex diseases, it becomes less powerful.

80. 80
SEGREGATION ANALYSIS
• Segregation analysis estimates the genetic model of a trait by
looking at multigenerational family data.
• The components of a genetic model are
1. Transmission probabilities (the probability that a parental
genotype transmits a particular allele to an offspring);
2. Penetrance for each genotype; and
3. Allele frequencies in the population (to determine prior
probabilities of genotypes when inferring genotypes from
phenotypes)

81. 81
SEGREGATION ANALYSIS
• Segregation analysis is a prerequisite for linkage analyses.
• Segregation analysis reveals
1. Mendelian inheritance patterns (autosomal or sex-linked and
recessive or dominant);
2. Nonclassical inheritance (mitochondrial diseases, genomic
imprinting, parent of origin effect, genetic anticipation etc); or
3. Non-Mendelian inheritance

82. 82
LINKAGE STUDIES
• The genes that make up the genetic component of a disease
etiology can be localized by linkage (cosegregation) and
following association studies identify the disease gene and
its allele contributing to disease risk.
• Linkage studies aim to obtain a crude chromosomal location
of the gene or genes associated with a phenotype of
interest, e.g. a genetic disease or an important quantitative
trait.
• Linkage studies are used for coarse mapping as they have a
limited genetic resolution. If two markers are close, there will
not be much recombination between them and they will
cosegregate.

83. 83
ASSOCIATION STUDIES
• Association studies at the population level are the next step
for fine mapping.
• Linkage disequilibrium (LD) is the foundation of association
studies.
• Association studies focus on population frequencies
• The assumption is that the genetic marker studied is close
enough to the actual disease gene and this will result in an
allelic association at the population level
• As opposed to linkage studies, families with multiple affected
individuals are not required and no assumptions are made
about the mode of inheritance of the disease. In addition,
association studies have considerable statistical power to
detect genes of weak effects unlike linkage studies in

84. 84
ASSOCIATION STUDIES
• Association studies at the population level are the next step
for fine mapping.
• Linkage disequilibrium (LD) is the foundation of association
studies.
• Association studies focus on population frequencies
• The assumption is that the genetic marker studied is close
enough to the actual disease gene and this will result in an
allelic association at the population level
• As opposed to linkage studies, families with multiple affected
individuals are not required and no assumptions are made
about the mode of inheritance of the disease. In addition,
association studies have considerable statistical power to
detect genes of weak effects unlike linkage studies in

85. Role of genetics in
Preventive and Social
Measures
85

86. 86
Health
Promotional
Measures
Eugenics
Negative
Positive
Euthenics
Genetic
Counselling
Prospective
Retrospective
Others
Consanguineous
Marriages
Late Marriages
Early
Diagnosis and
Treatment
Detection of
genetic
carriers
Prenatal
Diagnosis
Screening of
newborn
infants
Recognizing
pre-clinical
cases
Specific
Protection

87. Conclusion
Medical genetics and public health share a focus on populations
in practice, disease, and policymaking. While the effective integration of
genetics and public health services is a key to effective disease
intervention, it will be essential for clinicians, consumers, and
policymakers to understand the germane issues to ensure optimal
results. Understanding the functions of genes and the significance of
variation in specific genes will require researchers to learn how those
genes and their gene products interact with metabolic, nutritional, and
behavioral factors and with exposures to various chemical, physical, and
infectious agents.
Incorporation of genetic screening into a comprehensive public
health program that transcends individual clinical specialties may permit
development of an effective framework aimed at reducing morbidity and
mortality from adult-onset chronic diseases 87

88. Conclusion
Realization of the important role of genes in disease etiology
now challenges the traditional perspective. The sequencing and
annotation of the human genome carry broad practical implications for
the application of genetic testing to the mainstream practice of dentistry
A challenge facing the dental community is to develop
appropriate discourse that will guide initiatives to incorporate genetic
testing into the profession in a responsible manner.
Clearly, the expansion of genetic testing to the arena of
predictive testing of disease risk, prognosis, and response to therapy
will be an important component of health care in the future. When this
broader umbrella of genetic testing is considered, it is reasonable to
envision its playing a significant role in the mainstream of routine dental 88

89. 89
Thank You