this is lecture on genetic diseases prepared for my students, it is also useful to any person interested in genetics.

1. 1
Genetic diseases
by Dr.Hayelom k
Final year Pathology resident
Jimma university medical center
hayelomk21@gmail.com

2. Continued…
• Contents:
1. Introduction
2. Mutation
3. Categories of Genetic Disease
4. Diagnostic Approach
5. Genetic Counseling

3. 1. Introduction
• Human genome project- about 100,000 genes.
• All diseases involve changes in gene structure
or expression.
• DNA and RNA microarrays- analysis of human
diseases.
• Two classes of genes- Structural(Protein
coding)& Regulatry genes

4. 1.1. Human Genetic Make up.
• Genome
• Chromosomes
• DNA+ Histone
• dNT
• Bases + Deoxyribose sugar + Phosphates
• A, G, T, C

5. The Cell

6. Nucleus
☺DNA: arranged in chromosomes
(network of granules = nuclear chromatin)
☺ RNA: spherical intra nuclear structure(s)
nucleolus / nucleoli

7. DNA structure

8. DNA

9. Continued…

10. 1.2. Terminologies
• Chromosomes- DNA + Histones forming thread
like structures in the nucleus.
• DNA- The store of genetic information.
• Gene- A segment of DNA sequences on the
chromosome that codes for protein.
• gene Locus: specific site of a gene on the
chromosome. Since the chromosomes exist in
pairs, genes are also paired.

11. Continued…

12. chromosomes
Composed of double coils of DNA which Exist in
pairs – homologous: 22 autosomal + 1sex
chromosomes
Genes, specific base sequences in the chromosome
which code for specific information's
12

13. Sex chromosomes
☺ Genetic sex = composition of X and Y
☺ Large X: many genes, many activities
☺ Small Y: almost entirely male sexual
differentiation.
☺ Female: XX, male XY
☺ One X randomly inactivated and nonfunctional
after first week of embryonic development
☺ Same inactivated X in descendant cells

14. karyotype
14

15. Gene locus
• 23 paired chromosomes
• P&Q arms (short &long)
• Regions , 1,2 or 3
• Bands
• Sub bands
• e,g
12q22,1
15

16. Alleles: alternate forms of a gene can occupy
the same locus (homozygous, heterozygous)
Recessive gene: expressed only when
homozygous
Dominant gene: expressed whether
homozygous or heterozygous,
both expressed when co-dominant
Sex-linked gene: only X-linked in males, most
are recessive, homozygous (no allele on Y)
16

17. 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

18. Human Genome
☺ 3 billion+ pairs of DNA nucleotides
☺ ~ 50,000 – 100,000 genes
☺ Protein-coding Genes = <10% of human genome
☺ Exons: parts of the DNA chain that code for specific
proteins
☺ Introns: the parts in-between the exons
☺ Both exons and introns are transcribed but only the
exons are translated (introns are removed from mRNA
before leaving nucleus)
☺”Junk DNA”: no obvious function but 80% expressed

19. Central dogma
19

20. mRNA and t RNA

21. 21

22. Continued…
• Hereditary(familial) or Genetic disorders-
Derived from one's parents, transmitted in
the gametes through the generations.
• Congenital- Born with(just present at birth )
may be genetic or not.

23. 2. Mutation
• Permanent changes in the DNA.
• Are the bases of genetic diseases.
• Can occur
Spontaneously during cell division.
Induced by mutagens(Radiation, infections &
chemicals)

24. Continued…
• Can affect
Germ line cells (ovum and gametocyte)- genetic
disease.
Somatic cells- may cause cancer and some
congenital diseases.
Embryonic cells- mosaicism

25. Classification of mutations
1) Genome mutation – loss or gain of whole
chromosome (monopsony, trisomy)
e.g. 47,xy, 45,xy
2) Chromosome mutation – rearrangement of
genetic
material & give rise to visible structural changes
in
chromosome
3) Gene mutation – majority of mutation with
hereditary disease
25

26. Gene mutation
– Results in partial or complete deletion of
gene, more often affect single gene
– has three types
A, point mutation
B. deletion and insertion
C. tri nucleotide repeat mutations
26

27. A, 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
types of point mutation
– Missense mutations
– nonsense mutations
– Silent mutations

28. Missense mutation
• Change in single base pair results in changing
the amino acid
• e,g sickle cell anemia
• GAG (glutamic) GUC(valine)
28

29. Nonsense mutation
substation of one base stops the
transcription
Ex. βo – thalassemia
substation of one base stops the transcription
29

30. Silent mutation
• Point mutations which don’t have change in
the amino acids
UUU UUC
but both of the UUU&UUC codes for the same
amino acid[phenylalanine].
30

31. B, Deletions and insertions
31
insertion or deletion of one or two base
pairs alters the reading frame of the DNA
strand resulting in Frameshift mutations
If the number of base pairs involved in a
deletion is three or a multiple of three,
frameshift does not occur

32. Deletion and insertion can result in one of the
following:
Coding sequences Frame shift changing
Non frame shift changing
None coding sequences- Promoter &
enhancer deletions

33. Frame shift mutations
33

34. C,Trinucleotide repeat mutations
• Trinucleotide repeat mutations - these
mutations are characterized by amplification of
a sequence of three nucleotides.
–E.g. in fragile X syndrome, there are 250 to
4000 tandem repeats of the sequence CGG
within a gene called FMR1. In normal
populations, the number of repeats is small,
averaging 29
34

35. 2.2. Mutation effect
• Mutation
• Abnormal protein/No protein/ Increased protein
• Abnormal metabolic processes
• Tissue injury
• Genetic diseases.

36. 3. Categories of Genetic Diseases
• All Genetic diseases generally fall into one of the
following 4 categories:
A.Mendelian disorders.
B. Chromosomal disorders.
C. Multifactorial disorders.
D.Single gene diseases with non classic
patterns of inheritance.

37. A. Mendelian Disorders
Features:
• Caused by a single mutant gene.
• Affects transcription, mRNA processing, or
translation
• May affect any type of protein →Disease.
• Show the classic mendelian patterns of
inheritance.
• Are uncommon.

38. Continued…
• Classification of mendelian disorders - based
on their patterns of inheritance.
1. Autosomal dominant inheritance.
2. Autosomal recessive inheritance.
3. X-linked recessive inheritance.

39. 1. Autosomal dominant inheritance
a. The criteria
b. Additional features.
c. Pathogenesis
d. Clinical examples

40. Continued…
a. Criteria
• The transmission of the trait is from generation
to generation without skipping.
• Except for new mutation, every affected child
will have an affected parent.
• Mating of affected heterozygote to a normal
homozygote, each child has a 50% chance to
inherit the abnormal allele & be affected & a
50 % chance inherit the normal allele.

41. Continued…
• The 2 sexes are affected in equal numbers.

42. Continued…
b. Additional features.
• New mutations
• Ex. Achndroplasia.
• Reduced penetrance.
• Variable expressivity- Phenotyic spectrum
• Ex. Neurofibromatosis type 1

43. Continued…
c. Pathogenesis
i. Loss of function- structural and regulator protein
.
- 50% reduction in these proteins.
- ex. LDL receptor and Collagen.
ii. Gain of function-
-much less common than loss of function
mutations.
-the mutant gene produces a toxic protein.
-ex. Huntington disease.

44. d. Clinical examples
Marfan syndrome
 Some variants of
Ehlers – Danlos
syndrome
Osteogenesis
imperfecta
Achondroplasia
Huntington disease
Neurofibromatosis
• Tuberous sclerosis
• Myotonic dystrophy
• Familial
hypercholesterolemia
• Hereditary
spherocytosis
• Familial polyposis coli
• Polycystic kidney
disease

45. Marfan syndrome
• A disorder of the connective tissues of the
body, manifested principally by changes in the
skeleton, eyes, and cardiovascular system.
• Prevalence is estimated to be 1 in 5000
• 75% of cases are familial and show autosomal
dominant inheritance
• The remainder are sporadic and arise from new
mutations

46. Continued…
Pathogenesis
• Defect in extra cellular glycoprotein fibrillin-1,
which forms a scaffolding for deposition of
elastin fibers.
• More than 500 distinct mutations in FBN1 gene
are known, most resulting in an abnormal
protein.
• This abnormal protein disrupts assembly of
micro fibrils.

47. Continued…
Clinical Signs
• Cardiovascular
o Dilatation and aneurysms of aorta
o Floppy mitral valve.
• Ocular
o Ectopia lentis

48. Continued…
• Skeletal
o Pectus excavatum
o Scoliosis
o Joint laxity.
o Ratio of the upper segment to the lower segment
of body is usually 2 SDs below mean for age, race,
and sex

49. Continued…

50. Continued…

51. Continued…
Diagnosis
• Clinical
Skeletal changes
Ectopia lentis
Aortic aneurysm (ultrasound or x-ray)
• Histology
Cystic medial necrosis of aorta (autopsy)
Dissecting aortic aneurysm most common cause
of death

52. Continued…
• Genetic and molecular
Problematic because there are 500 distinct
mutations.
Detection of fibrillin defects in cultured skin
fibroblasts and DNA analysis of the gene are
now available from several laboratories.

53. Familial hypercholesterolemia
• Mutations in the gene for LDL receptor → No
functional LDL receptor → Leads to:
i. Impaired plasma LDL clearance.
ii. Impaired IDL uptake by the liver.
iii. Increased scavenger receptor

56. 2. Autosomal recessive inheritance
a. Criteria:
If the trait is rare, parents & relatives other than
siblings are usually normal.
Mating of 2 phenotypically normal
heterozygotes, the segregation frequency with
each pregnancy is 25% homozygous normal, 50%
heterozygous normal, & 25% homozygous
affected.

57. Continued…
• All children of two affected parents are
affected.
• Both sexes are affected in equal numbers.

58. Continued…

59. Continued…
b. Additional features
Less variable expressivity than autosomal
dominant.
Commonly show complete penetrance.
Show signs & symptoms early in life.

60. Continued…
c. Pathogenesis
• Loss of function mutations which result in
decreased enzyme proteins.
• Homozygotes → No normal enzyme → Disease.
• Heterozygotes →Equal amounts of normal &
defective enzymes → Cells with half the normal
amount of the enzyme function normally →No
disease.

61. d. Clinical examples
Non enzyme protein mutation
• Sickle cell anemia
• Thalassemias
• Congenital adrenal
hyperplasia
• Cystic fibrosis
• Wilson disease.
• Hemochromatosis
Enzyme protein mutation
• Phenylketonuria
• Galactosemia
• Homocystinuria
• Lysosomal storage diseases
• Alpha 1 antitrypsin
deficiency
• Glycogen storage disease

62. Lysosomal Storage Diseases
• Lysosomes contain acid hydrolases that
catabolize the breakdown of complex
molecules.
• Lysosomes may contain.
substances from cellular organelles (autophagy).
bacteria and other exogenous material
(heterophagy)

63. Continued…
• Lysosomal storage diseases result from the lack
of any protein essential for their function.
Lack of lysosomal enzyme.
Dysfunctional enzyme.
Defective post-translational processing of
enzyme.

65. Continued…
E.G : Gaucher disease
• Is the most common lysosomal storage
disorder.
• Is a disorder of lipid metabolism caused by
mutations in the gene encoding
glucocerebrosidase.
• Deficiency of glucocerebrosidase→
Accumulation of glucocerebroside
mononuclear phagocyte system &
the central nervous system

66. Continued…
• Type I (chronic non neuronopathic)
• Type II ( acute neuronopathic) &
• Type III (Juvenile).

67. Continued…
clinically manifests by
• Splenomegaly → Hypersplenism → Pancytopenia.
• Hepatomegaly
• Generalized lymphadenopathy
• Pathologic fractures & bone pain due to erosion of the
bone.
• First appearance of sings & symptoms in adult life.
• Progressive disease which is compatible with long life.

69. Continued…
Diagnosis
• Morphology
Gaucher cell is characteristic
• Glucocerebrosidase assay
Diagnostic of homozygous disease
Heterozygote values overlap with normal
• Genetic
Presence of 150 alleles complicates genetic diagnosis

70. Sickle-Cell Anemia
(Sickle-Cell Disease)
• The most common
genetic disorder
among black people
• About 1 in 500
African Americans
has sickle-cell
anemia.
• Carriers are said to
have sickle-cell trait

71. Sickle-Cell Anemia
• Caused by an abnormal
gene on chromosome 11
• The gene is for one of the
polypeptide chains in
hemoglobin, a protein
found in red blood cells
that is responsible for
transporting oxygen
through the bloodstream

72. Sickle-Cell Anemia
• Sickle-cell anemia causes hemoglobin to clump
within red blood cells, which distorts their shape
from the normal biconcave disc to a sickle shape.
• People with sickle-cell trait have
some abnormal hemoglobin but do
not have the symptoms of sickle-cell
disease.

73. Symptoms of Sickle-Cell Anemia
• Abnormal hemoglobin cannot
deliver oxygen as efficiently to
cells as in healthy individuals
– Fatigue
– Dizziness
– Headaches
• Sickled red blood cells cannot move as easily through capillaries as
normal RBCs
• Chronic pain, especially in bones
• Reduced immune response to infections
• Strokes

74. 3. X-linked recessive inheretance
• All sex-linked disorders are X-linked.
• There is no Y-liked inheritance because Y-linked
mutations result in infertility.
• X-linked disorders can be either recessive
(almost all) or dominant (rare).
• No male-to-male (i.e. father-to-son)
transmission of the trait

75. Continued…

76. b. Clinical examples
Diabetes insipidus
Lesch-Nyhan syndrome
Fragile X syndrome
Duchenne muscular dystrophy
Hemophilia A & B

77. Continued…
• Chronic granulomatous disease of childhood
• Glucose-6-phosphate dehydrogenase (G6PD)
deficiency
• Agammaglobulinemia
• Wiskott -Aldrich syndrome

78. B. Chromosomal(Cytogenetic) Disorder
• Occur much more frequently than is generally
appreciated.
• Found in 50% of early spontaneous abortuse & in
0.5% of live born infants.
• Caused by abnormal structure & number of
chromosomes.

79. Continued…
1. Karyotype.
2. Types of chromosomal abnormalities.
3. Autosomal Cytogenetic disorders.
4. Sex chromosome Cytogenetic disorders
.

80. 1. Karyotype.
• A photomicrograph of the chromosomes of an
individual arranged in the standard classification
(i.e. metaphase chromosomes arranged in order
of decreasing length).
• Chromosome can be identified based on its
banding pattern & length.

81. Continued…

82. Continued…

83. Shorthand system of notations
• First the total number of chromosomes is given.
• Second the sex chromosome constitution is given.
• Finally any abnormality is described.
E.g. 1. A normal female karyotype is 46,XX.
E.g. 2. A female with trisomy 21 is described as
47,XX,+21.

85. 2. Types of chromosomal abnormalities.
• Chromosomal anomalies may be
numerical(increase or decrease in number ) or
structural(e.g translocations ).
• Can affect autosomal or sex chromosomes
• Rarely seen clinically compared to real
occurrence

86. 1. Numeric Abnormalities
The normal 46,xx or xy is cold euploid
Can be :
a. Aneuploidy
 is addition or loss of 1 or rarely 2 chromosomes.
 E,g , 47,XX
b. Polyploidy
 is the addition of complete haploid sets of chromosomes.
 2n,3n….where n is haploid sets of chromosome
 E.g 69,XXY

87. Count…
Numerical anomalies Results from
anaphase lag- one normal cell and one
monosomic cell.
non disjunction- result in trisomic, tetrasomic…
cells.

88. Nondisjunction in meiosis

89. II. Structural anomalies
 This are rearrangements of genetic material within
or between different chromosomes.
 Result from breakage of chromosomes followed by
loss or rearrangement of genetic material.
 Are of the following types.
a. Deletion
b. Iso chromosome formation
c. Inversion.
d. Translocation.

90. a. Deletion
Is loss of a portion of a chromosome.
Has the following subtypes.
i. Terminal deletions.
 arise from one break.
E.g. 46,XX, del(18p14)

91. ii. Interstitial deletions
Arise from 2 breaks, loss of the interstitial
acentric segment & fusion at the break sites.

92. iii. Ring chromosomes
Arise from breaks on either side of the
centromere & fusion at the breakpoints on the
centric segment. E.x. 46,XX, r(15).

93. b. Isochromosome formation
Results when one arm of a chromosome is lost &
the remaining arm is duplicated, resulting in a
chromosome consisting of 2 short arms only or 2
long arms only.
 The arm on one side of the centromere is a mirror
image of the other.

95. c. Inversion
• Is reunion of a chromosome broken at 2
points, in which the internal segment is
reinserted in an inverted position.
• Inversion can be pericentric or para centric

97. d. Translocation.
 Is an exchange of chromosomal segments
between 2 non-homologous chromosomes.
i. Reciprocal (balanced translocation)
ii. Robertsonian translocation

98. 1.Reciprocal (balanced translocation)

99. ii. Robertsonian translocation

100. 3. Autosomal Cytogenetic disorder
practical examples of chromosomal disorders :
Down syndrome- Chromosome 21
Edward syndrome- Chromosome 18
Patau syndrome- Chromosome 13
Chromosome 22q11 deletion syndrome

101. Down Syndrome (Trisomy 21 )
• Most common chromosomal disorder
• Affects 1 in 750 newborns overall, but is related to
maternal age.
• Usually results from meiotic nondisjunciton of
chromosome 21
• 4% result from Robertsonian translocation of
chromosome 21 to another chromosome.
• 1% result from mitotic nondisjunction of
chromosome 21 during early embryogenesis:
mosaics

102. Continued…

103. Clinical Features of Down Syndrome

104. Trisomy 21 (Down)

105. Prenatal Diagnosis
• Amniocentesis
Most common modality
Performed at 15-17 weeks gestation
• Chorionic Villus Sampling (CVS)
Second most common
Performed at 10-12 weeks gestation
• Percutaneous umbilical blood sampling (PUBS)
Performed in second and third trimesters
Usually prompted by ultrasound abnormalities of
fetus

106. 4. Sex chromosome Cytogenetic disorders
Imbalances of X-chromosomes are better tolerated
than those of autosomes.
Lyonization – Murray Lyon
During 16th day of embryonic life one X-
chromosome in females is randomly inactivated
Inactivation persists in all subsequent cells.
• Increased number of X-chromosomes in either
males or females lead to mental retardation

107. (Murray) Barr body

108. Klinefelter Syndrome(47,XXY)
• A male hypogonadism that occurs when there are
two or more X-chromosomes and one or more Y-
chromosomes
• Incidence is 1 in 500 male births
• Usually (82% of cases) 47,XXY
maternal (60%) or paternal (40%) nondisjunction
during meiotic divisions
• 15% are mosaics, usually 46,XY/47,XXY

110. Clinical Features
• Testicular abnormality does not develop before
puberty.
Seminiferous tubules are atrophic resulting in
reduced spermatogenesis, infertility, small firm
testes, and increased FSH
Testosterone levels are reduced
-impotence and increased LH
-lack of secondary male sexual
characteristics
• Mental retardation is unusual but IQ may be below
normal
• Mosaics are less severely affected

113. Turner syndrome(45,X0)
• This is loss of one of the sex chromosome
• Genetically and phenotipicaly females but are
infertile
• Secondary sexual characters are not well
developed
• Could be due to monogenic or chromosomal
.

116. Turner syndrome

117. C. Multifactorial Disorder
• Are more common than mendelian disorders.
• Result from the combined actions of
environmental factors & 2 or more mutant
genes having additive effects (i.e. 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.

118. Continued…
• Diabetes mellitus
• Hypertension
• Ischemic heart disease
• Gout
• Schizophrenia

119. Continued…
• Bipolar disorders
• Neural tube defects
• Cleft lip/ cleft palate
• Pyloric stenosis
• Congenital heart disease, etc….

120. Features:
1. The risk of expressing a multifactorial disorder
partly depends on the number of inherited
mutant genes.
2. The risk of recurrence of the disorder is the
same for all first degree relatives of the affected
individual & this is in the range of 2-7%.

121. Continued…
3. The concordance rate for identical twins is 20 –
40%.
4. When one child is affected, the chance that the
next child will be affected is 7%.
5. When 2 children are affected, then the chance
that the next child will be affected increases to 9%.

122. D. Single gene diseases with non classic
patterns of inheritance.
A. Diseases caused by mutations in mitochondrial
genes.
E.g. Leber hereditary optic neuropathy
B. Diseases associated with genomic imprinting
E.g Angelman syndrome
C. Disorders caused by triplet repeat mutations
E.g. Fragile X syndrome

123. 4. Diagnostic Approach

124. Continued…

125. Continued…

126. Continued…

127. Polymerase Chain Reaction

128. DNA Microarray
Examine how active thousands of genes are at any given time.

129. Continued…

130. 5. Genetic Counseling
• Definition
• Principles of Genetic Counseling
i. Diagnosis
ii. Education
iii. Supportive counseling
iv. Follow-up

131. Definition
• A communication process between a healthcare
professional trained in genetics and an individual
or family affected by or at risk for an inherited
disorder.
Principles of Genetic Counseling
• To provide appropriate information for families
• Genetic counselors follow several guiding
principles.
• Include providing an accurate diagnosis,
education of family members, supportive
counseling, and follow-up.

132. Continued…
I. Diagnosis
• The single most important aspect of genetic
evaluation.
• Wrong information result in further harm
• The genetics team may order diagnostic testing
for a suspected condition.
• Counselors inform families of the benefits, risks
and limitations of such testing before testing
begins.

133. Continued…
ii. Education
The known and unknown aspects of a particular
disorder.
Its natural history
Prognosis for affected individuals.
Existing treatment and/or management options.
Recurrence risk

134. Continued…
iii. Supportive counselling
• Depending on the seriousness of the disease,
parents may feel
Guilt or shame
Grief and anger
Depression

135. Continued…
iv. Follow up
Summary of the important medical and genetic
information in a letter to the family so that it can
be accessed at any time.
Further counseling if questions arise or emotional
issues become overwhelming.
For referral preparation

136. Continued…
References
• Robbins, Basic Pathology 8th edition.
• Genetics Home Reference -
http://ghr.nlm.nih.gov/ Handbook
• http://web.udl.es/usuaris/e4650869/docencia
/GenClin/content/recursos_classe_(pdf)/revisi
ons...