GENETIC
BASIS OF
DISEASE part-1
Genetic basis of disease
part 1- objectives
a. The role of genetic causes of diseases.
b. Common modes of genetic disorders such as single
gene defect, polygenic inheritance, etc.
c. Discuss the complex traits and diseases which
predispose and modify common diseases.
D. Describe the process of gene-gene interaction and
gene-environment interactions
Suggested readings: Robbins’s basic pathology: 8th
edition, page 226 – 232
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The role of genetic causes of diseases
Are ALL diseases “genetic”?
Are all diseases “environmental”?
How does “congenital” fit in? How does “immune” fit in?
How does this fit in with DEG-INF-NEO?
1. GENETICALLY DETERMINED
2. ENVIRONMENTALLY DETERMINED
3. BOTH NATURE
Genetic promises to unlock secret of Inherited and
Acquired human disease.
 All disease involve changes in genes structures or
expression.
 Genetic makeup influences immune response&
Susceptibility to microbial infection.
Etiology of diseases.
•For any condition the overall
balance of genetic and
environmental determinants
can be represented by a
point somewhere within the
triangle.
Classification of Human genetic disorders
1.
Complex multigenic (Polygenic) disorders
(Multifactorial)
+ environment
2.
Disorders related to mutations in single
genes (Monogenic) with large effects
(Mendelian).
1.
Chromosomal disorders
Multifactorial (Polygenic)
“Environmental” influences act on a genetic predisposition
. One organ system affected.
- Environmental: Drugs, Chemical, Radiation, infections, etc..
Single gene
Dominant/recessive pedigree patterns (Mendelian).
Structural proteins, enzymes, receptors, transcription
factors.
Chromosomal
Multiple organ systems affected
Inherited or de novo
Very low
Continuum of penetrance.
There is a continuum of penetrance from fully penetrant
conditions, where other genes and environmental factors have
no effect, through to low-penetrance genes that simply play a
small part, along with other genetic and environmental factors,
in determining a person’s susceptibility to a disease.
Single gene disorders



Single gene mutations, following classical Mendelian inheritance patterns
Most of these are hereditary and familial. (High risks to relatives).
Dominant/recessive pedigree patterns
Some isolated cases due to new dominant mutations
Structural proteins, enzymes, receptors, transcription factors.
MENDELIAN inheritance patterns;
(1) Autosomal dominant (AD)
(2) Autosomal recessive (AS)
(3) Sex-linked- involve x-chromosome.
I:1
II:1
II:2
I:2
II:3
II:5
II:6
III:1
I:1
AA
I:2
AB
I:1
II:1
II:1
AA
II:2
AB
II:2
II:3
III:2
III:3
I:2
II:4
II:5
II:6
II:7
II:8
II:9
II:10
II:11
II:12
II:13
III:9
III:10
III:11
III:12
II:14
II:15
II:3
BB
III:1
?
III:4
III:5
III:6
III:7
III:8
III:13
III:14 III:15
III:1
BB
Tom
IV:1
IV:2
IV:3
IV:4
IV:5
IV:6
IV:7
IV:8
IV:9
IV:10
III:2
IV:1
I:3
IV:11
IV:12
IV:13
III:16 III:17
II:8
Single-gene disorders with non-classic
inheritance
Certain single-gene disorders does not follow classic mendelian
principles. This group of disorders can be classified into four
categories:
1.
Diseases caused by trinucleotide-repeat mutations (e.g.
Fragile-X Syndrome).
2.
Disorders caused by mutations in mitochondrial genes
(e.g. Leber hereditary optic neuropathy) (Ovum>sperm)
3.
Disorders associated with genomic imprinting= silencing
inactivates either the maternal or paternal allele.
4.
Disorders associated with gonadal mosaicism-mutation
that occurs during early (embryonic) development
What are the effects of Single genetic
disorders?
1.
Enzyme defect (Most of them, e.g. PKU- “AR”)
Accumulation of substrate
B. Lack of product
C. Failure to inactivate a protein which causes damage
Enzyme defect which increases drug susceptibility:
A.
2.
3.
4.
G6PD Primaquine.
Receptor/transport protein defect (Familial
Hypercholesterolemia- “AD”).
Structural protein defect (Marfan, Ehl-Dan)- “AD”
A. Structure
B. Function
C. Quantity
Mutations

MUTATIONS- are permanent disorders in individual’s
DNA (essential single gene changes) in amount or
function or both.  interfere e protein synthesis 
responsible for causing illnesses, fall in two categories of
genes:
1. Mutations in germ cells: are transmitted to the
progeny and can give rise to inherited diseases.
2. Mutations in somatic cells –
Not transmitted to progeny, but important in causation
of malignant transformation and some congenital
diseases.
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Complex Multifactorial Disorders
Caused by interactions between variant forms of
genes, lifestyle and environmental factors.
• Disorders result from interaction between environmental &
genetic factors.
A genetic variant that has at least two alleles and
occurs
in atin nature
least (more
1% of
population
is called a
• Often
polygenic
thanthe
one gene
is responsible).
polymorphisms.
•
• Environmental factors play a significant role in precipitating the
disorder in genetically susceptible individuals.
Polymorphism are not-specific to certain groups of
•Tend
to cluster in has
families.
diseases,
a small effect and is of low
Do not show Mendelian inheritance
penetrance
•
•Examples of mutifactorial disorders: obesity, DM, hyperchlosterolemia .
hypertension
• Example of common diseases
involved in this mode:
e.g. HTN, DM, CHD, AT,Gout, MANY, MANY, MORE
Complex Multifactorial Disorders
Criteria for assigning a disease to this mode of
inheritance:
1.
Cluster in families, no clear-cut pattern of
inheritance.
2.
Exclusion of mendelian & chromosomal modes of
transmission.
3.
Environmental factors influences are important
in the pathogenesis of these diseases
significantly modify the phenotypic expression
of complex traits e.g. (DM-II& obesity)
4.
variable expressivity and reduced penetrance.
5.
Difficult to study and treat.
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Gene-Gene interaction (GXG)
GXG means gene expression is depend on expression
(presence or absence) of other gene and also certain
genes can mask other gene expression, (influence,
controlled or governed),may involve 2 or>more pairs.
Example:
Sex and Heredity Male pattern baldness Dominant
in males, recessive in females
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Gene-Environment interaction (GXE)
Definition: define as a different effect of
environmental factor in people with different
genotype.

People with different genotype could differed in
Susceptibility to health effect after certain
exposure; Not everyone is equally susceptible to
stressors, toxins and trauma.
 Response to medications- Different people to
respond to the same drugs in different ways
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What does it mean to have a genetic
predisposition to a disease?
A genetic predisposition (called genetic susceptibility) is
an increased likelihood of developing a particular disease
based on a person’s genetic makeup.
A genetic predisposition results from specific genetic
variations that are often inherited from a parent.
These genetic changes contribute to the development of
a disease but do not directly cause it.
Some people with a predisposing genetic variation will
never get the disease while others will, even within the
same family.
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Genetics
G×E
interaction
Environment
Health
The end
Mutation
3 common categories “examples” of mutations:
1.
Genome mutations: (whole chromosome)
Chr by loss or gain of a whole chromosome e.g.
trisomy 21, commonly due to nondisjunction.
2.
Chromosome mutations
Chr by rearrangement of genetic material within
the chromosome giving rise to visible changes in
chromosome structure e.g. translocations
3.
Gene mutations:
–
Submicroscopic genetic changes.
–
Chr by deletion or insertion, substitution of
nucleotide bases within a gene.
–
Common examples includes
1.
Point mutation
2.
Frameshift mutation.
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3.
Trinucleotide repeat mutation.
I. Point Gene mutations
1. Point mutation with coding sequences:
is due to a single nucleotide substitution or base pair of
a DNA sequence, lead to the replacement of one a.a by
another, involved DNA transcription- e.g. sickle cell
anemia.
Silent mutation:
Altered DNA codes for the same amino acid
Mis-sense mutation
Altered DNA codes for a different amino acid.
Nonsense mutation:
Altered DNA codes for a stop codon that causes permanent
termination of protein synthesis
2. Point mutation within non-coding sequences
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Gene mutations (Cont.)
II. Frameshift mutations:
Insertion or deletion of one or more nucleotides base
pair.
Changes the reading frame of the DNA strand.
Example:
In Tay-Sachs disease defective lysosomal enzyme.
IIII. Tri-nucleotide repeat mutations:
Errors in DNA replication
Cause amplification of a sequence of three
nucleotides (e.g. CGG), which disrupts gene
function.
E.g. in Fragile X syndrome – repeats of CGG within
gene called FMR1
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