1. GENETIC BASIS OF DISEASE part-1 IMPOSSIBLE!!!!! HORROR!!!!!
ANXIETY!!!!!!
DREAD!!!!!
INADEQUACY!!!!!

2. 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

3. 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?
GENETICALLY DETERMINED
ENVIRONMENTALLY DETERMINED
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.
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?
50% of early abortuses  chromosomal abnormality.
1% of all newborn infants possess gross chromosomal abnormality.

4. Etiology of diseases.
For any condition the overall balance of genetic and environmental determinants can be represented by a point somewhere within the triangle.

5. Classification of Human genetic disorders
Complex multigenic (Polygenic) disorders (Multifactorial)
Disorders related to mutations in single genes (Monogenic) with large effects
(Mendelian).
Chromosomal disorders
+ environment

6. Multifactorial (Polygenic)
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

7. Continuum of penetrance.
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.
Very low

8. 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
I:2
II:1
II:2
II:3
II:5
II:6
II:8
III:1
III:2
IV:1
I:1 AA
I:2 AB
II:1
II:2
II:3 BB ?
III:1
Tom
I:2
I:1
I:3
II:1
II:2
II:3
II:4
II:5
II:6
II:7
II:8
II:9
II:10
II:11
II:12
II:13
II:14
II:15
III:1
III:2
III:3
IV:1
IV:2
IV:3
IV:4
III:4
III:5
IV:5
IV:6
IV:7
III:6
III:7
IV:8
IV:9
IV:10
III:8
III:9
III:10
III:11
III:12
III:14
III:13
III:15
III:16
III:17
IV:11
IV:12
IV:13

9. 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:
Diseases caused by trinucleotide-repeat mutations (e.g. Fragile-X Syndrome).
Disorders caused by mutations in mitochondrial genes (e.g. Leber hereditary optic neuropathy) (Ovum>sperm)
Disorders associated with genomic imprinting= silencing inactivates either the maternal or paternal allele.
Disorders associated with gonadal mosaicism-mutation that occurs during early (embryonic) development

10. What are the effects of Single genetic disorders?
Enzyme defect (Most of them, e.g. PKU- “AR”)
Accumulation of substrate
Lack of product
Failure to inactivate a protein which causes damage
Enzyme defect which increases drug susceptibility: G6PD Primaquine.
Receptor/transport protein defect (Familial Hypercholesterolemia- “AD”).
Structural protein defect (Marfan, Ehl-Dan)- “AD”
Structure
Function
Quantity

11. 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.
kmutation:
most commonly due to nondisjunction
Chromosome mutations:
usually because of translocations. Increases with increasing maternal age
Gene mutation ( mendelian disorders)
Frameshift mutation: examples:
Tay-Sachs disease:
insertion of a four- base pair leads to synthesis of defective hexosaminidase A
Cystic fibrosis:
deletion of a three-nucleotide base causes formation of defective transmembrane regulatory protein for chloride ions

12. College of Medicine- Majmaah University
Dr. Sherif Saleh
Complex Multifactorial Disorders
Caused by interactions between variant forms of genes, lifestyle and environmental factors.
A genetic variant that has at least two alleles and occurs in at least 1% of the population is called a polymorphisms.
Polymorphism are not-specific to certain groups of diseases, has a small effect and is of low penetrance
Example of common diseases involved in this mode:
e.g. HTN, DM, CHD, AT,Gout, MANY, MANY, MORE
Disorders result from interaction between environmental &
genetic factors.
Often polygenic in nature (more than one gene is responsible).
Environmental factors play a significant role in precipitating the
disorder in genetically susceptible individuals.
Tend to cluster in families.
Do not show Mendelian inheritance
Examples of mutifactorial disorders: obesity, DM, hyperchlosterolemia .
hypertension
Module of the Principles of Health & Disease

13. Complex Multifactorial Disorders
Criteria for assigning a disease to this mode of inheritance:
Cluster in families, no clear-cut pattern of inheritance.
Exclusion of mendelian & chromosomal modes of transmission.
Environmental factors influences are important in the pathogenesis of these diseases significantly modify the phenotypic expression of complex traits e.g. (DM-II& obesity)
variable expressivity and reduced penetrance.
Difficult to study and treat.
Several normal phenotypic characteristics are governed by multifactorial inheritance, such as hair color, eye color, skin color, height, and intelligence
For example, type II diabetes mellitus has many of the features of a multifactorial disorder.
It is well recognized clinically that individuals often first manifest this disease after weight gain. Thus, obesity as well as other environmental influences unmasks the diabetic genetic trait. Nutritional influences may cause even monozygous twins to achieve different heights. The culturally deprived child cannot achieve his or her full intellectual capacity.

14. 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

15. 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

16. 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.

17. Genetics
G×E interaction
Environment
Health
h^2
The end

18. Mutation 3 common categories “examples” of mutations:
Genome mutations: (whole chromosome)
Chr by loss or gain of a whole chromosome e.g. trisomy 21, commonly due to nondisjunction.
Chromosome mutations
Chr by rearrangement of genetic material within the chromosome giving rise to visible changes in chromosome structure e.g. translocations
Gene mutations:
Submicroscopic genetic changes.
Chr by deletion or insertion, substitution of nucleotide bases within a gene.
Common examples includes
Point mutation
Frameshift mutation.
Trinucleotide repeat mutation.

19. 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

20. 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