GENETIC DISORDERS

By:
Dr: Manhal AbdulGadir
MBBS U of K
MD clinical pathology U of K
 OBJECTIVES
• By the end of this lecture students should be able to:
• Revise the normal human genetics and cell division
• Differentiate between mutations and cytogenetic
disorders
• Describe the Mendalian inheritance patterns and
examples of each
• Describe the types of mutations and cytogenetic
disorders
• Describe some of the common genetic disorders and
their clinical features
 The DNA molecule
• Deoxyribonucleic
acid (DNA):
Located in the
nucleus, rapped up
in structures called
chromosomes

46 Chromosomes -23
Pairs in every cell
 What is a gene?
• A part of the DNA
that codes for a
protein.

• Not all the DNA

codes for proteins.

• 20000 to 25000
genes in the human
genome.
 Genome
☺ Sum total of all genes contained in a cell’s
chromosomes
☺ Identical in all cells
☺ Not all genes are expressed in all cells
☺ Not all genes are active all the time
☺ May code for enzymes or other functional
proteins, structural proteins, regulators of
other genes
 DNA replication occurs during the
life of a cell = the Cell Cycle
• DNA replicates (makes a copy of itself) to
produce DS chromosomes
• During this time, the cytoplasmic contents
also duplicate
• Spindle tubules form to aid
in the process of cell division
– Mitosis in body cells
– Meiosis in sex cells
 Definitions
- Locus: specific site of a gene on the chromosome.

- Alleles: alternate forms of a gene can occupy the

same locus

- Recessive gene: expressed only when homozygous

- Dominant gene: expressed when heterozygous

- Sex-linked gene: only X-linked in males

 Genetic diseases
• Traditionally - 3 types of diseases
• 1. Genetically determined
• 2. Environmentally determined
• 3. BOTH.
• up to 20% of pediatric in-patients have genetic
abnormality
• about 50% of spontaneous abortuses have chromosomal
aberration
• only mutations that are not lethal are reservoir of genetic
diseases
• SINGLE GENE DEFECTS
✓At the level of genes
• CYTOGENETIC ABNORMALITIES
✓At the level of chromosomes
• MULTIGENIC DISORDERS
✓Gene polymorphism and environmental
factors
Mutations in Protein-Coding Genes
• Mutation refers to permanent changes in the
DNA.
1-Point mutations:
• Result from the substitution of a single nucleotide
base by a different base, resulting in the replacement
of one amino acid by another in the protein product.
• Mutation in the β-globin chain of hemoglobin giving
rise to sickle cell anemia is an excellent example of a
point mutation.
2-Frameshift mutations :
Occur when the insertion or deletion of one or two base
pairs alters the reading frame of the DNA strand.
3-Trinucleotide repeat mutations:
Amplification of a sequence of three
nucleotides. Eg: Fragile X syndrome (mental
retardation)
 Epigenetic Changes
• Epigenetic changes are those involving modulation of
gene or protein expression in the absence of
alterations in DNA sequence (i.e., mutation) or
structure of the encoding gene.
1- Alterations in the methylation
2- Histone modifications
3- Post translation modifications.
 Disorders of Autosomal Dominant
Inheritance
• Disorders of autosomal dominant inheritance
are manifested in the heterozygous state, so at
least one parent in an index case usually is
affected; both males and females are affected,
and both can transmit the condition
• Some patients do not have affected parents.
Such patients owe their disorder to new
mutations involving either the egg or the
sperm from which they were derived.
• In many conditions, the age at onset is
delayed, and symptoms and signs do not
appear until adulthood (as in Huntington
disease).
Eg: Autosomal Dominant Disorders
• Familial hypercholesterolemia.
• Polycystic kidney disease.
• Hereditary spherocytosis.
• Marfan syndrome.
• Huntington disease.
 Disorders of Autosomal Recessive
Inheritance
• They occur when both of the alleles at a given
gene locus are mutants; therefore, such
disorders the siblings have one chance in four
of being affected (i.e., the recurrence risk is
25% for each birth).
• Onset is frequently early in life.
 Eg :Autosomal Recessive Disorers

• Cystic fibrosis
• Phenylketonuria (Phenylalanine hydroxylase Enzyme)
• Tay-Sachs disease (Hexosaminidase Enzyme)
• Severe combined immunodeficiency( Adenosine
deaminase Enzyme)
• α- and β-Thalassemias
• Sickle cell anemia
 X-Linked Disorders
• All sex-linked disorders are X-linked. No Y-linked
diseases are known as yet.
• Most X-linked disorders are X-linked recessive and
are characterized by the following:
-They are transmitted by heterozygous female
carriers only to sons, who of course are
hemizygous for the X chromosome.
- Heterozygous females rarely express the full
phenotypic change, because they have the paired
normal allele
• An affected male does not transmit the
disorder to sons, but all daughters are carriers.
Sons of heterozygous women have one chance
in two of receiving the mutant gene.
 Eg:X-linked Recessive Inheritance

-Hemophilia A Factor VIII Coagulation

-Duchenne/Becker muscular dystrophy
Dystrophin: Structural protein
-Fragile X syndrome
 Diseases Caused by Mutations in Genes
Encoding Structural Proteins
Marfan Syndrome:
• A connective tissue disorder of autosomal dominant
inheritance.
• Mutation affecting fibrillin, secreted by fibroblasts, is
the major component of microfibrils found in the
extracellular matrix.
• Skeletal abnormalities, ocular change is bilateral
dislocation, or subluxation, of the lens secondary to
weakness of its suspensory ligaments
• Cardiovascular system: mitral valve prolapse
 Ehlers-Danlos Syndromes
• Are a group of diseases characterized by
defects in collagen synthesis or structure.
• The mode of inheritance encompasses both
autosomal dominant and recessive patterns.
• Because the abnormal collagen fibers lack
adequate tensile strength, the skin is
hyperextensible and joints are hypermobile.