Genetic Basis of Diseases

Professor Dr Ahsan Kazmi

Pathology Department
Al Nafees Medical College
Islamabad
Introduction
• Genome mapping was a big achievement 2003
• Hope for treatment of genetic diseases
• Genetic engineering
• The genes that code for proteins are only
20-25,000
• miRNAs- microRNA- small RNA molecules/genes that do not code for
protein but can have important regulatory functions eg inhibit gene
expression
What are Genetic disorders ?

Genetic disorders are illnesses caused by abnormalities in

• Chromosome structures

• Genetic sequences
Some definitions….
• Genetics
Study of single/ few genes with their phenotypic
effects
• Genomics
Study of all the genes in the genome and their
interactions
Some definitions….
• Proteomics
Study of all the proteins expressed in a cell/tissue
• Epigenetics
Study of heritable changes in gene expression not
caused by alterations in DNA sequence
Some definitions….
• Hereditary Transmitted in germline
• Familial Runs in families- multifactorial
• Congenital Present at birth, “born with”
• Bio-informatics
Analysis of the patterns of expression of genes/proteins with
the assistance of computers
Types of Genetic disorders:
1. Mutations in single genes
-Mendelian
-Non-classic
2. Chromosomal disorders
-Numerical
-Structural
Types of Genetic disorders:
3. Complex multigenic (multifactorial)
gene polymorphisms+ environment
4. Heterogeneous group
A heterogeneous group of genetic disorders that, like
Mendelian disorders, involve single genes but do not
follow simple Mendelian rules of inheritance.
Single gene disorders
Need to know:
• Allele one of the gene locus
• Codon 3-base sequences of DNA/RNA
that specify a single amino acid
• Epigenetic Changes in phenotype/gene
due to factors other than DNA
changes, eg methylation or
histone modification
Some definitions….
• Exon=region of the gene that codes for a protein
• Intron=non coding region in a gene
• Penetrance=likelihood of altered phenotype in a person with
mutant gene
Some definitions….

• Point mutation=substitution of a single DNA base

in the normal DNA sequence

• Stop codon=a codon that leads to termination of a

protein
1. Mendelian Disorders- Single Gene
Mutations
Includes many uncommon conditions, such as the
• Storage diseases and
• Inborn errors of metabolism
All resulting from single-gene mutations of large
effect.
• Most of these conditions are hereditary and
familial
2. Multifactorial

• Both genetic and environmental factors influence/

condition the expression of a disease
• Some of the most common disorders of humans,
such as Hypertension and diabetes mellitus are
included in this group
3. Abnormalities in the Chromosomes

• Disorders that are the consequence of

• Numeric or
• Structural abnormalities
in the chromosomes
4. Heterogeneous group

• A heterogeneous group of genetic disorders that Involve single genes

• But do not follow simple Mendelian rules of inheritance
4. Heterogeneous group
These single gene disorders with non-classic inheritance patterns
include those:

1. Resulting from triplet repeat mutations

2. Arising from mutations in mitochondrial DNA In which the
transmission is influenced by an epigenetic phenomenon called
genomic imprinting
Nature of genetic
abnormalities contributing to
disease

• Several types
• Affect structure/function of protein
• Disrupting cellular homeostasis & contributing to
disease
Mutation
Mutation:
• A permanent inheritable change in amount or structure of DNA
• Can be inherited or occur spontaneously
This may be
• Germline (inherited disease)

• Somatic (congenital disease/cancers)

Types of Mutations

• Genome mutations:
• loss/gain of whole chromosomes (trisomy/monosomy)
• Chromosomal mutations:
• structural changes in chromosomes
• Gene mutations:
• single genes affected
 Gene mutations
Can be:
- Point mutations
one nucleotide base substituted
- Frameshift mutations
one/more bases inserted or deleted, leading to
alterations in the reading frame (instructions
are mis-interpreted)
Gene Mutations
Point mutations in coding
sequences
• Single nucleotide substitutions can
Missense, eg change the triplet base code and yield
a different amino acid in the final
sickle cell anemia protein product. This occurs in
missense type of mutations

• Single Nucleotide Substitution 

Nonsense ,eg • stop codon 
thalassemia • resulting protein truncated with loss
of normal activity
Point mutations in non-coding
sequences
• These are Required for Transcription as they serve
as sites for the attachment of transcription factors

• Mutations in these areas will hamper transcription

Frameshift mutations

• Deletions/ insertions in coding regions result

in alterations in reading frame

• Abnormal proteins result

Trinucleotide repeat mutations

• Amplification of a sequence of three nucleotides,

involving G and C usually

• Gene expression is blocked

Eg in fragile X syndrome, FMR gene has about

29 repeats of CGG; here 250-4000 repeats occur
Present
& future