Session 16:

Genetic disorders
Dr. Alex Simon (MD)

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 Learning tasks
At the end of this session, students are expected to be
able to:
• Describe genetic mutations.
• Classify genetic diseases.
• Describe genetic diseases related to gene mutation.
• Describe genetic diseases related to chromosomal
abberation.
• Describe genetic diseases related to multifactorial
inheritance.

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 Mutations
• Refers to permanent changes in the DNA.
• Mutations that affect germ cells are transmitted to the
progeny and may give rise to inherited diseases.
• Mutations in somatic cells are not transmitted to the
progeny but are important in the causation of cancers and
some congenital malformations.
Types:
1. Point mutations.
2. Frameshift mutations.
3. Trinucleotide repeat mutations.
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 Point mutations
• Mutations involving a change in a single nucleotide
base within a gene e.g. Sickle cell disease.
Types:
1. Silent mutation.
– Altered DNA codes for the same amino acid without
changing the phenotypic effect.
2. Missense mutation
– Altered DNA codes for a different amino acid, which
changes the phenotypic effect.
3. Nonsense mutation.
– Altered DNA codes for a stop codon that causes premature
termination of protein synthesis. 4
 Frameshift mutations
• Frameshift mutations occur when the insertion or
deletion of one or two base pairs alters the reading
frame of the DNA strand.
• Two classes of genes, proto-oncogenes and tumour
suppressor genes, regulate normal cell growth and
differentiation.
• Mutations affecting these genes, most often in somatic
cells, are involved in the pathogenesis of tumours.
• Example: Tay-Sachs disease.

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 Trinucleotide repeat mutations
• Mutations are characterized by amplification of a
sequence of three nucleotides.
• There is expansion of these normally repeated
sequences to more than 100 repeats.
– Normally, 3 nucleotides are repeated 20-30 times.
• All affected sequences share the nucleotides guanine
(G) and cytosine (C).
– Cause amplification of a sequence of three nucleotides
(e.g., CAG), which disrupts gene function
• Example: Fragile X syndrome.
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 Major categories of Genetic
disorders
1. Those related to mutant genes (single gene
mutation) of large effect (Mendelian disorders).
2. Those arising from chromosomal aberrations
(Cytogenetic disorders).
3. Diseases with complex multigenic inheritance
(Multifactorial disorders).

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 Major categories of Genetic
disorders cont…
1. Mendelian disorders.
• All resulting from single-gene mutations of large
effect.
• Most of these conditions are hereditary and familial.
• Mutations involving single genes follow one of three
patterns of inheritance:
i. Autosomal dominant disorders.
ii. Autosomal recessive disorders.
iii. Sex linked (X-linked) disorders.

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Major categories of Genetic disorders
cont…
2. Genetic disorders due to chromosomal
aberrations.
• Disorders that are the consequence of numeric or
structural abnormalities in the chromosomes.
3. Multifactorial genetic disorders.
• Multifactorial, or complex, inheritance implies that
both genetic and environmental influences condition
the expression of a phenotypic characteristic or
disease.

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Diseases caused by single-gene defects (Mendelian disorders)

• Mutations involving single genes follow one of three

patterns of inheritance:
1. Autosomal dominant disorders.
2. Autosomal recessive disorders.
3. Sex linked (X-linked) disorders.

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 Autosomal dominant disorders

Characteristics of Autosomal dominant disorders.

1. Manifests in the heterozygous state, so at least one
parent in an index case usually is affected
– Characterised by one faulty copy of gene (i.e. mutant
allele) in any autosome and one copy of normal allele
2. 50% chance of passing on the disease to the next
generation.
3. Both males and females are affected.
– The gene is situated on autosomes, not sex chromosomes.
4. Both can transmit the condition.
5. No carrier state. 11
Autosomal dominant disorders cont…

• One dominant mutant gene (A) is required to express

the disorder.
• Heterozygotes (Aa) express the disorder.
• Homozygotes (AA) are often spontaneously aborted.
• In many cases, structural proteins are affected by
the mutation in ADD.

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 Examples of Autosomal dominant
disorders
1. Marfan’s syndrome. 8. Ehlers – Danlos
2. Retinoblastoma. syndrome.
3. Osteogenesis 9. Tuberous sclerosis.
imperfecta. 10. Myotonic dystrophy.
4. Neurofibromatosis. 11. Familial
hypercholesterolemia.
5. Achondroplasia.
12. Hereditary spherocytosis.
6. Huntington disease.
13. Familial polyposis coli.
7. Polycystic kidney
disease. 14. Von Willebrand disease.

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 Autosomal recessive disorders

Characteristics of Autosomal recessive disorders:

1. Individuals must be homozygous for the mutant
recessive gene (aa) to express the disorder.
– Homozygotes are symptomatic early in life.
2. Heterozygous individuals (Aa) are asymptomatic
carriers.
– The dominant gene (A) overrides the mutant recessive gene
(a).
3. Both parents must be heterozygous to transmit the
disorder.
4. Both males and female may carry the gene. 14
 Autosomal recessive disorders
cont…
5. 50% risk that the gene will be passed to any child in
accordance with Mendel’s first law of segregation.
6. The trait parents (heterozygous carriers) are usually
not affected, but siblings may show the disease.
7. Associated with consanguineous marriage.
8. In many cases, enzyme proteins are affected by the
mutation in ADR.

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 Examples of Autosomal recessive
disorders
1. Sickle cell anemia. 9. Galactosemia.
2. Thalassemias. 10. Homocystinuria.
3. Albinism. 11. Lysosomal storage
4. Congenital adrenal diseases (Gaucher
hyperplasia. disease).
5. Wilson disease. 12. Alpha 1 antitrypsin
deficiency e.g. Cystic
6. Hemochromatosis. fibrosis.
7. Phenylketonuria. 13. Glycogen storage
disease.
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 Sex linked (X-linked) disorders

• X-linked disorders are caused by mutations in genes

on X-chromosome, derived from either
– One of the two X-chromosomes in females or
– The single X-chromosome of the male.
• Therefore, all sex-linked disorders are, in fact, X-
linked disorders.
• No Y-linked diseases are known as yet.
• X-linked disorders can be either recessive (almost all)
or dominant (rare).
– Most of X-linked disorders are X-linked recessive.
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 Characteristics of Sex linked
(X-linked) disorders
1. Transmitted by heterozygous female carriers only to
sons (sons are hemizygous for the X chromosome).
– Therefore only males are clinically abnormal.
2. Heterozygous females rarely express the full
phenotypic change, because they have the paired
normal allele.
– However, because of the inactivation of one of the X
chromosomes in females (usually the normal allele)
permitting full expression of the disease in heterozygous
females.
3. The daughters of a carrier mother have 50% risk of
carrying the trait. 18
 Characteristics of Sex linked
(X-linked) disorders cont…
3. Sons of heterozygous women have one chance in
two (50%) of receiving the mutant gene.
– They are hemizygous affected 50% of the time (i.e. the
sons have 50% chance of being affected)
4. An affected male does not transmit the disorder to
sons, but all daughters are carriers.
– Daughters are normal heterozygous carriers 50% of the
time & normal homozygotes 50% of the time.
5. Affected daughters are produced by matings of
heterozygous females with affected males.

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 Examples of Sex linked
(X-linked) disorders
1. Haemophilia A. 7. Glucose-6-phosphate
2. Duchenne muscular dehydrogenase
dystrophy. deficiency.
3. Diabetes insipidus. 8. Bruton’s
4. Colour blindness. agammaglobulinaemia.
5. Chronic 9. Wiskott -Aldrich
granulomatous disease. syndrome.
6. Fragile X syndrome. 10. Lesch-Nyhan
syndrome.

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 Chromosomal
(Cytogenetic) disorders
• Cytogenetic disorders may result from alterations in
the number or structure of chromosomes and may
affect autosomes or sex chromosomes.
• These disorders are divided into two (2) types:
1. Numerical abnormalities
2. Structural abnormalities.

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 Characteristics of Chromosomal
(Cytogenetic) disorders
1. Chromosomal disorders may be associated with
absence (deletion, monosomy), excess (trisomy), or
abnormal rearrangements (translocations) of
chromosomes.
2. In general, loss of chromosomal material produces
more severe defects than does gain of chromosomal
material.
3. Excess chromosomal material may result from a
complete chromosome (as in trisomy) or from part
of a chromosome (as in robertsonian translocation).
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 Characteristics of Chromosomal
(Cytogenetic) disorders
4. Imbalances of sex chromosomes (excess or loss) are
tolerated much better than autosomes imbalances.
5. Sex chromosomal disorders often produce subtle
abnormalities, sometimes not detected at birth.
– Infertility, a common manifestation, cannot be diagnosed
until adolescence.
6. In most cases, chromosomal disorders result from de
novo changes (i.e., parents are normal, and risk of
recurrence in siblings is low).
– Uncommon but important exception to this principle is
exhibited by the translocation form of Down syndrome.
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 Numerical abnormalities
• In humans, the normal chromosome count is 46.
• Somatic cell is diploid or 2n (46 chromosomes)
• Germ cells have haploid or 1n (23 chromosomes).
• Any exact multiple of the haploid number (n) is
called euploid.
• Haploid, diploid or polyploid are euploids.

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 Numerical abnormalities cont…
• Polyploidy is a multiple of haploid number e.g.
triploid or 3n (69 chromosomes), tetraploid or 4n (92
chromosomes).
– Occurs in megakaryocytes and dividing liver cells.
– Polyploidy in somatic cells results in a spontaneous
abortion.
• Aneuploidy is the number of chromosomes which is
not an exact multiple of haploid number
Examples:
– Hypodiploid or 2n-1 (45 chromosomes) monosomy,
– Hyperdiploid or 2n+1 (47 chromosomes) trisomy.
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 Numerical abnormalities cont…
• The chief causes of aneuploidy is:
1. Nondisjunction of a homologous pair of
chromosomes at the first meiotic division or
2. Failure of sister chromatids to separate during the
second meiotic division or during mitosis in somatic
cells, leading to the production of two aneuploid
cells.
• Failure of pairing of homologous chromosomes
followed by random assortment (anaphase lag) can
also lead to aneuploidy.
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 Numerical abnormalities cont…
• When nondisjunction occurs at the time of meiosis,
the gametes formed have either an extra chromosome
(n + 1) or one less chromosome (n − 1).
• Fertilization of such gametes by normal gametes
would result in two types of zygotes:
1. Trisomic: with an extra chromosome (2n + 1).
2. Monosomic: with a less chromosome (2n − 1).

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 Numerical abnormalities cont…
Mosaicism
• Describes the presence of two or more populations of
cells with different complements of chromosomes in
the same individual.
• Two chromosomally different cell lines are derived
from a single fertilized egg.
• Occurs due to nondisjunction of chromosomes during
mitotic division in the early embryonic period.
• Mosaicism affecting sex chromosomes is common,
whereas autosomal mosaicism is not.
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 Structural abnormalities
• Structural changes in the chromosomes usually result
from chromosomal breakage followed by loss or
rearrangement of material.
• During cell division (meiosis as well as mitosis), certain
structural abnormalities of chromosomes may appear.
• These may occur during gametogenesis and then
transmitted to all somatic cells and cause hereditary
transmissible disorders.
• May produce somatic cell mutations and result in
changes varying from no effect to some forms of cancers.
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 Patterns of chromosomal
rearrangement after breakage
1. Translocation.
– Reciprocal.
– Robertsonian.
2. Isochromosomes.
3. Deletion.
4. Inversions.
5. A ring chromosome.

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 Examples of Chromosomal disorders
involving autosomes
1. Down's syndrome.
– Trisomy 21, Karyotype: 47XX, 47XY.
– Maternal age has a strong influence.
– The most common cause of trisomy.
– Due to meiotic nondisjunction.
2. Edward's syndrome.
– Trisomy 18 type, Karyotype: 47XX or 47XY.
3. Patau's syndrome.
– Trisomy 13, Karyotype: 47XX, 47XY.

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 Examples of Chromosomal disorders
involving sex chromosomes
1. Turner's syndrome.
– Monosomic, Karyotype: 45X0.
– Due to nondisjunction.
2. Klinefelter's syndrome.
– Trisomic, Karyotype: 47XXY.
– Due to nondisjunction.
– Phenotypically male.
3. XYY syndrome.
– Caused by paternal nondisjunction.
– Associated with aggressive (sometimes criminal) behavior.

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 Multifactorial genetic disorders
• Result from the combined actions of environmental
factors & two or more mutant genes having additive
effects.
– The greater the number of inherited mutant genes, the more
severe the phenotypic expression of the disease.
• The disease clinically manifests only when the
combined influences of the genes & the environment
cross a certain threshold.

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 Examples of multifactorial genetic
disorders
• Hypertension.
• Diabetes mellitus.
• Congenital heart disease.
• Cleft lip and cleft palate.
• Pyloric stenosis.
• Schizophrenia.
• Bipolar disorders.
• Neural tube defects.
• Coronary heart disease (Ischemic heart disease).
• Gout. 34
 Key points
• Mutations are permanent change in DNA.
• Single-gene mutations of large effect is seen in
Mendelian disorders.
• Autosomal dominant disorders are characterized by
expression in heterozygous state.
• Both copies of a gene are mutated in Autosomal
recessive disorders.
• Sex linked disorders are transmitted by heterozygous
females to their sons, who manifest the disease.
• Combined effect of genetic and environmental
influences in multigenic genetic disorders.
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 Review questions
1. Explain three (3) types of mutations.
2. List (3) categories of genetic diseases.
3. Mention five (5) examples of autosomal recessive
disorders.
4. List five (5) characteristics of sex linked disorders.
5. Explain five (5) patterns of chromosomal
rearrangement after breakage.

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 References
• Bezabeh M.; Tesfaye A.; Ergicho B. et al (2004):
General pathology lecture notes for Health Sciences
students. Ethiopia Public Health Training Initiative.
Pg. 98-136.
• Goljan E.;(2007): Rapid Review Pathology (2th Ed.)
Elsevier Saunders, USA. Pg. 85-97.
• Kumar V. ; Abbas A. K. ; Aster J. C.;(2013): Robbins
and Contran Pathologic Basis of Disease (9th Ed.)
Elsevier Saunders, USA. Pg. 216-220, 234-241.
• Mohan H.;(2010): Text book of Pathology (6th Ed.)
Jaypee Brothers Medical Publishers, India. Pg. 257-
263. 37