2. Revision on normal human genetics
• Genetic information is stored in DNA.
• The typical normal human cell contains 46 chromosomes {i.e. 23 pairs of
chromosomes: 22 homologous pairs of autosomes & one pair of sex
chromosomes (XX or XY)}.
• They have the same gene loci in the same sequence, though at any specific
locus they may have either identical or slightly different forms, which are
called alleles.
• Each chromosome is in turn composed of a very long unbranched molecule
of DNA bound to histones & other proteins.
• DNA is composed of two very long complementary chains of
deoxynucleotides.
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3. DNA has two basic functions:
1. it provides the genetic information for protein synthesis.
The portion of DNA that is required for the production of a protein is called a
gene
2 .It transmits the genetic information to the daughter cells & to the
offspring of the individual.
DNA →→transcription →→mRNA→→translation →→PROTEIN.
↓
↓replication
DNA
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4. • Genetic information is transmitted to the daughter cells under two
circumstances:
1. Somatic cells divide by mitosis, allowing the diploid (2n) genome to
replicate itself completely in conjunction with cell division.
2. Germ cells (sperm & ova) undergo meiosis – a process that enables
the reduction of the diploid (2n) set of chromosomes to the haploid
state (1n).
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5. Mutations
• Mutation is permanent changes in the primary nucleotide sequence
of DNA regardless of its functional significance.
• occur spontaneously during cell division or are caused by mutagens
such as radiation, viruses, & chemicals.
• can occur in germ line cells (sperm or oocytes) or in somatic cells or
during embryogenesis.
• Germ line mutations can be passed from one generation to the next
& thus cause inherited disease. Somatic mutations do not cause
hereditary disease but they may cause cancer (because they confer a
growth advantage to cells) & some congenital malformations.
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6. Conti….
• classified into the following three categories based on the extent of
the genetic damage:
1. Genome mutations : are gain or loss of one or more whole chromosomes.
E.g. aneuploidy & polyploidy.
2. Chromosome (cytogenetic) mutations : are due to rearrangement of genetic
material in a chromosome which results in structural changes in the
chromosome.
E.G Philadelphia chromosome”—translocation t(9;22) between the BCR and
ABL genes in chronic myeloid leukemia
3. Gene mutations
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7. Gene mutations
• cause most of the hereditary diseases
• may affect a single base (more common) or they may affect a larger
portion of a gene.
• have the following types:
A. Single base pair change (Point Mutation)
B. Deletions & Insertions
C. Expansions of repeat sequence
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8. A. Point mutation (Single base pair change)
- is the substitution of one base for another.
- includes the following types:-
1. Silent mutations
2. Missense mutations: changes the codon for one amino acid to the
codon for another amino acid.
EG. mutation which causes sickle cell anemia.
3. Nonsense mutations :changes the codon for an amino acid to a stop
codon, leading to termination of translation of the mRNA transcript & a
truncated protein. E.g. β-thalassemia
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9. B. Deletions & insertions
Deletions & insertions of one or two bases within coding sequences
lead to frame shift mutations.
Deletion or insertion of three or a multiple of three base pairs within
coding sequences cause abnormal protein.
Deletions affecting the promoter/enhancer sequences (i.e. in the
noncoding regions)leads to promoter / enhancer mutations.
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10. C . Expansion of repeat sequences
• Show expansion of a sequence of 3 nucleotides.
• Normally, 3 nucleotides are repeated 20-30 times. Trinucleotide
repeat mutation is when there is expansion of these normally
repeated sequences to more than 100 repeats.
• Example myotonic dystrophy, Huntington’s disease, fragile X
syndrome,
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12. Categories of genetic diseases
Genetic diseases generally fall into one of the following 4 categories:
A. Mendelian disorders
B. Chromosomal disorders
C. Single gene diseases with non classic patterns of inheritance.
D. Multifactorial disorders
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13. Mendelian disorders
• Each mendelian disorder is caused by a single mutant gene.
can be classified into the following based on their patterns of
inheritance:
1. Autosomal dominant inheritance
2. Autosomal recessive inheritance
3. X-linked recessive inheritance
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14. Autosomal dominant disorders
• Heterozygous state
• Both sexes can be affected and transmit the condition
• Reduced penetrance and variable expressivity can affect clinical picture of the
condition
• Neurofibromatosis 1
• The age at onset of most of diseases is delayed, and symptoms
and signs do not appear until adulthood
• A 50% reduction in the normal gene product is associated with clinical signs and
symptoms
• Never enzymes
• Membrane receptors, transport proteins
• Structural proteins
• Example: familial hypercholesterolemia, neurofibromatosis
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16. Pathology
• Cholesterol deposits
(xanthomas) and premature
atherosclerosis (coronary artery
disease)
• Heterozygous carriers have 2 – 3 x
raise in plasma cholesterol and are
asymptomatic to late adulthood
• Homozygous have 5x increased
risk and early dev’t of
atherosclerosis before age of 20
• Mutations in the LDL receptor
protein
• Impair the intracellular transport
and
catabolism of LDL and
accumulation of LDL cholesterol in
the plasma
• Conversion of ILD into LDL.
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17. Disorders of Autosomal Recessive Inheritance
• Homozygous state
• Carrier parents, diseased siblings
• Recurrence risk is 25% for each birth
• If the mutant gene occurs with a low frequency in the population, there is a
strong likelihood that the affected patient (the proband) is the product of a
consanguineous marriage.
• They make up the largest group of mendelian disorders
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18. Conti….
• The expression of the defect tends to be more uniform than in
autosomal dominant disorders
• Complete penetrance is common
• Onset is frequently early in life
• Although new mutations for recessive disorders do occur, they are
rarely detected clinically
• Enzymes are affected by the mutation
Example : Sickle cell anemia ,Thalassemias ,Congenital adrenal
hyperplasia.
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19. Sickle cell anemia
• Mutation in β-globin (a single
amino acid substitution, valine
instead of glutamate, in) that
results in a tendency for
deoxygenated HbS to self-associate
into polymers
• In parts of Africa where malaria is
endemic, the gene frequency
approaches 30% as a result of a
protective
effect against Plasmodium
falciparum malaria
• Sickle cell trait, 40% HBS,
dominated by HBA, no sickling
• Homogenous, sickle on
deoxygenation, initially reversible.
• Later irreversible and hemolysis
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20. Pathobiology and consequences
• Sluggish capillary flow
• Spleen and the bone marrow
• Inflamed tissues
• Clinically
• Unremitting course punctuated by
sudden crises
• Chronic hemolytic anemia
• Increased hemoglobin
breakdown and heme
• Vascular obstructions
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22. X-Linked Disorders
• Sex-linked disorders are X linked
• Most X-linked disorders are X-linked recessive , no Y-linked
• Heterozygous female carriers
• all daughters are carriers
• Females do not express full phenotype
• can be either recessive (almost all) or dominant (rare).
• No male-to-male (i.e. father-to-son) transmission of the trait (in all
sex-linked inheritance).
• Affected daughters are produced by matings of heterozygous females
with affected males.
• Example : hemophilia A and B
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25. Introduction
• Alterations in the number or structure of chromosomes
• May affect autosomes or sex chromosomes
• 1 in 200 newborn infants has some form of chromosomal abnormality
• Karyotypes are given as total number of chromosomes, followed by
the sex chromosome complement, and then abnormalities in
ascending numerical order
• E.g. 47,XY,+21
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26. Numeric Abnormalities, aneuploidy
• Causes
• Nondisjunction of a homologous
pair of chromosomes at the first
meiotic division
• Failure of sister chromatids to
separate during the second
meiotic division
• Polyploidy – always aborted
• Non disjunction
• (n –1) or (n+1)
• Once fertilized, either trisomy (2n+
1) or monosomy (2n- 1) is
produced.
• Mosaicism
• One or more populations of cells,
some with normal chromosomal
complement, others with extra or
missing chromosome
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29. Trisomy 21 (Down Syndrome)
• This is the most common chromosomal disorder (1 in 700 births)
• 95% complete extra chromosome 21 (e.g., 47,XY,+21).
• 4% have extra chromosomal material derived from a parental chromosome
bearing a translocation of the long arm of chromosome 21 to chromosome 22
or 14.
• Mosaic variants make up approximately 1% of all cases
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30. Clinical features
• Flat faces with oblique palpebral fissures and epicanthic folds;
simian hand creases.
• Severe mental retardation.
• Forty percent will have congenital heart disease, especially
endocardial cushion defects, responsible for the majority of
deaths in infancy and childhood.
• Tenfold to twentyfold increased risk of acute leukemia.
• Abnormal immune responses leading to recurrent infections
and thyroid autoimmunity.
• Premature Alzheimer disease
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32. • 40% of the patients have congenital heart disease, endocardial
cushion, including atrial septal defects, atrioventricular valve
malformations, and ventricular septal defects
• Atresias of the esophagus and small bowel
• 10 – 20x increased risk of developing acute leukemia
• Virtually all patients with trisomy 21 older than age 40 develop
neuropathologic changes characteristic of Alzheimer disease, a
degenerative disorder of the brain
• Abnormal immune responses serious infections, particularly of the
lungs, and to thyroid autoimmunity
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nondisjunction of a homologous pair of chromosomes at the first meiotic division or a failure of sister chromatids to separate during the second meiotic division
