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Principles of Diagnosis of
Genetic Diseases using
Molecular and Cytogenetic
Dr Pupak Derakhshandeh, PhD
Ass Prof Medical Science of Tehran University
English Website: http://medicine.tums.ac.ir/en/Professor_cv.aspx?lt=8&uid=5984
Persian Website: http://medicine.tums.ac.ir/fa/Professor_cv.aspx?lt=8&uid=889
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Cytogenetics
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Karyotype )46, Xy)
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How Chromosome
Abnormalities Happen?
Meiosis
Mitosis
Maternal Age
Environment
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Meiosis
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Chromosome abnormalities
 Abnormality
of chromosome
number or structure:
Numerical
 Structural
Abnormalities
Abnormalities
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Down Syndrome
Trisomy 21
Down Syndrome (Trisomy 21(
Trisomy 2(
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Down Syndrome
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Frequency of Dysmorphic Signs in
Neonates with Trisomy 21
Dysmorphic sign
Frequency (%)
Flat facial profile
Poor Moro reflex*
Hypotonia
Hyperflexibility of large joints
Loose skin on back of neck
Slanted palpebral fissures**
90
85
80
80
80
80
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*
*
**
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Frequency of Dysmorphic Signs in
Neonates with Trisomy 21
Dysmorphic sign
Frequency (%)
Dysmorphic pelvis on radiograph
Small round ears
Hypoplasia of small finger
70
60
60
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Estimated risk of Down syndrome
according to maternal age
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The risk of having a child with
Down syndrome
 1/1,300
for a 25-year-old woman;
 at age 35, the risk increases to 1/365
 At age 45, the risk of a having a child
with Down syndrome increases to
1/30
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Ultrasound
During the first trimester of the majority of
pregnancies
 measure the size of the fluid area at the back
of the fetus’s neck
 nuchal translucency or NT
 increasing size of the NT:


a greater risk of the fetus having Down’s
syndrome
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Ultrasound
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Trisomy 18, 47 Ch.
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Trisomy 18, 47 Ch.
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Trisomy 18, 47 Ch.
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incidence of about 1 in 3,000
30 percent of affected newborns die within
the first month
50% by two months
and 90% by one year.
severe mental retardation
microcephaly
overlapping fingers, and rocker bottom feet
Neurologically they are hypertonic
Other common malformations include
congenital heart, kidney, .... abnormalities.
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Trisomy 13 (XX/XY, 47 Ch)
has an incidence of 1 in 5,000
44 percent of affected newborns succumb in the
first month of life
and 69% by six months
Only 18% of the babies born with trisomy 13
survive the first year
microcephaly
microophthalmia (small eyes)
cleft lip or cleft palate
polydactyly (extra fingers)
congenital heart defects
urogenital defects
brain malformations
severe mental retardation.
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Turner Syndrome (45 , X)
45, X
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Turner Syndrome
(45, X)
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Turner syndrome
• Only females
• One X chromosome
• Or has two X chromosomes but one is
damaged
• Short stature
• Delayed growth of the skeleton
• Sometimes heart abnormalities
• Usually infertile due to ovarian failure
• Short neck with a webbed appearance
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Kleinefelter47/XXY
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Kleinefelter
XXY
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Klinefelter syndrome (47, XXY)
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In boys and men
47 chromosomes with XXY sex
chromosomes
XXY is one of the most common
chromosomal abnormalities
1 in 500 male births
the most common genetic cause of male
infertility
Often : undiagnosed : variation in clinical
presentation
Small testes , insufficient production of
testosterone , and infertility
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Fragile X
Syndrome
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Fragile X Syndrome

1 in 3,600 males

It is second only to Down Syndrome
as a cause of mental retardation
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Fragile X Syndrome

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(CGG)n trinucleotide expansion in the FMR1
gene leading to the typical Martin-Bell
phenotype
Expansion of a (CCG)n repeat in the FMR2
gene corresponds to the FRAXE fragile site
but it is less frequent and lacks a
consistent phenotype
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a woman having amniocentesis
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AF (15. -16. weeks)
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CVS (10.-12. weeks)
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Ultrasonographic Findings Associated
with Fetal Down Syndrome
Chorionic villus sampling
10 to 12 weeks 0.5 to 1.5 %
Early amniocentesis
12 to 15 weeks 1.0 to 2.0 %
Second-trimester amniocentesis
15 to 20 weeks 0.5 to 1.0 %
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Chromosome abnormalities
 Abnormality
of chromosome
number or structure:
Numerical
Abnormalities
Structural
Abnormalities
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Structural Abnormalities

Deletions: A portion of the
chromosome is missing or deleted
(>5 Mb).
 Paraderwilli
Syndrome (Ch 15)
 Angleman Syndrome (Ch 15)
 Imprinting
effect
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Structural Abnormalities

Translocations: When a portion of
one chromosome is transferred to
another chromosome.
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 There
are two main types of
translocations.
 In a reciprocal
translocation, segments from
two different chromosomes
have been exchanged.
 In a Robertsonian
translocation, an entire
chromosome has attached to
another at the centromere.
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45
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Chronic myelogenous leukemia
(CML)

15% to 20% of leukemias in adults
incidence of 1 to 2 cases per 100,000
population
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fluorescence in situ hybridization (FISH)
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Autosamal
Recessive Disease
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Globin genes synthesis
Lessons from the thalasemia. Nature Reviews, Genetics, volume2, 2001
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.
The human globin locus
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Hematological values & a-Thalassemia
a
a
a
a
s
Molecular diagnosis of hemoglobin disorders, Clin. Lab. Haem. 2004, 26, 159–176
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The α-globin locus is shown with the ζand 2 α-globin genes on chromosome 16
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HbH Disease
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Mucopolysaccharides
Examples
 Hunter
syndrome (X-L)
 Hurler syndrome (AR)
 Scheie syndrome (AR)
 Sanfilippo syndrome (AR)
 Morquio disease (AR)
 Maroteaux-Lamy syndrome (AR)
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Hurler syndrome
type I
(Alpha-L-iduronate deficiency )
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Hurler syndrome (type I)
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Mucopolysaccharidosis I (MPS I) Disease
(Hurler, Hurler-Scheie, Scheie Syndromes)
Key Symptom Images
Hernia
Corneal
clouding
Coarse
facial
features
Claw hand
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Symptoms

Short stature
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Full lips with a thick, large tongue
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Increased body hair (hirsutism)
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Deafness
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Stiffness (in joints)
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Shortness of breath
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Abnormal bones of spine and claw hand
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Hunter syndrome type II
(Sulpho-idoronide sulphatase deficiency )
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Hunter syndrome type
II
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Sanfilippo syndrome type
III
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SMA
SPINAL
MUSCULAR
ATROPHY
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CLASSIFICATION

SMA TYPE I (Werdnig-Hoffmann)

SMA TYPE II (Classic)
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SMA TYPE III (Kugelberg-Welander)
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OTHER CLASSIFICATION
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Bone Diseases
OI
Osteogenesis
imperfecta
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Procollagen
Troprocollagen
Collagens
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X-linked Disease
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Severity of disease

Osteogenesis imperfecta:
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type II> type III> type IV> type I
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Hemophilia A/B
How is ’Hemophilia’ inherited?
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DuchenneMuscular
dystrophy
Waddling gait
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In the late stages of muscular dystrophy:
fat and connective tissue often replace
muscle fibers
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DMD
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