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GENETIC DISORDERS
Lecture 6
Nabil MTIROUI, MSc. PhD
Nondisjunction – a problem with meiosis
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A “junction” is a place of meeting or joining.
So, to “disjunct” is to unjoin – or separate…
During which phase of meiosis do the chromosomes
separate?
Anaphase I and
Anaphase II
So nondisjuction indicates that the chromosomes (or
chromatids) do not separate as they should…
Nondisjunction results in sex cells
Nondisjunction disorders
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During fertilization, a “normal” sperm is joined with a
egg that has either an extra or is missing a chromosome.
The chromosome involved will determine the disorder.
Larger chromosomes involved with nondisjunction will
often result in miscarriage.
The Karyotype…
Trisomies with the sex chromosomes
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Klinefelter syndrome : 47, XXY males. Male sex organs;
unusually small testes, sterile. Breast enlargement and
other feminine body characteristics. Normal intelligence.
Trisomies with the sex chromosomes
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47, XYY males : Individuals are somewhat taller than
average and often have below normal intelligence. At
one time (~1970s), it was thought that these men were
likely to be criminally aggressive, but this hypothesis
has been disproven over time.
Trisomy X: 47, XXX females. 1:1000 live births healthy and fertile - usually cannot be distinguished
from normal female except by karyotype
Trisomies with the sex chromosomes
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Monosomy X (Turner's syndrome): 1:5000 live births; the only
viable monosomy in humans - women with Turner's have only 45
chromosomes!!! XO individuals are genetically female, however, they
do not mature sexually during puberty and are sterile. Short stature
and normal intelligence. (98% of these fetuses die before birth)
Trisomies in Autosomes
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Patau syndrome (trisomy 13) : serious eye, brain,
circulatory defects as well as cleft palate. 1:5000 live
births. Children rarely live more than a few months.
Trisomies in Autosomes
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Edward's syndrome (trisomy 18): almost every organ
system affected 1:10,000 live births. Children with full
Trisomy 18 generally do not live more than a few
months.
Down’s syndrome
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Down syndrome (trisomy 21): The result of an extra copy of
chromosome 21. People with Down syndrome are 47, 21+. Down
syndrome affects 1:700 children and alters the child's phenotype
either moderately or severely:
Down Syndrome is correlated with age of mother but can also be
the result of nondisjunction of the father's chromosome 21.
Maternal age is an important factor…
Other genetic disorders
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Sickle Cell Anemia – this genetic disorder is autosomal
homozygous recessive (ss).
Autosomal means that it is NOT a gene on the sex
chromosomes and so males and females will have equal
inheritance.
Homozygous recessive means that the person will have two
recessive genes. This person must inherit a recessive gene
from both the mother and the father. (Both the mother and
father would be heterozygous).
S
s
Ss X Ss
S
SS
Ss
s
Ss
ss
Two heterozygous parents would have a 1 in 4 (25%)
chance of having a child with Sickle Cell Anemia.
Heterozygote Advantage
Sickle cell anemia is more common
in African Americans
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This is due to the fact that the
heterozygote (carrier) has an
increased resistance to malaria.
If you follow the family history of
the people that are carriers back
in time, most likely their ancestors
are from central Africa where
malaria was a problem hundreds
of years ago. The carriers were
more likely to have survived
malaria and passed their genes
on to their offspring. This has
kept this gene in the population.
The heterozygote has survival
advantage.
Tay Sach’s Disease
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Tay Sach’s Disease – this disorder is also autosomal
homozygous recessive. A baby with Tay Sach’s would
have to inherit a recessive gene from each parent.
Tt X Tt
T
t
T
TT
Tt
t
Tt
tt
Again, there is a 25% chance of these two parents
having a child with Tay Sach’s disease.
Cystic Fibrosis
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Cystic Fibrosis – this disorder is autosomal
homozygous recessive. A person with Cystic Fibrosis
had to have inherited a recessive gene from each
parent. Both parents would be carriers.
(heterozygous).
Cc
X
Cc
C
c
C
CC
Cc
c
Cc
cc
Again, there is a one in four chance of having a child
with Cystic Fibrosis.
Heterozygote advantage
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Cystic fibrosis is most common in Caucasians (whites)
whose ancestors can be traced back to western Europe.
As with the disease discussed above, the heterozygote
(carrier) has resistance to a disease. In this case, it is
Cholera. Cholera depletes the system of fluid very
rapidly and having slightly thicker body fluids is an
advantage in surviving Cholera.
Phenylketonuria (PKU)
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This disorder is autosomal homozygous recessive.
(Can you guess the inheritance pattern?). The person
would receive a recessive gene from each parent.
Commonly, both parents would be heterozygous
and would have a one in four chance of having a
child with PKU.
P
p
Pp X Pp
P
PP
Pp
p
Pp
pp
Hemophilia
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This disorder is caused by a sex-linked recessive gene. It has the
same inheritance pattern as colorblindness. Males will have this
disorder if they inherit the gene from only one parent (the
mother). Females would have to receive this gene from both
parents.
XH
Xh
XHXh x XHY
XH
XHXH XHXh
Y
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XHY
XhY
Neither parent has hemophilia, but the mother is a carrier
(heterozygous).
With a carrier mother and a normal father, the daughters have a
50% chance of being a carrier, but will NOT have hemophilia.
The sons have a 50% chance of having hemophilia.
Huntington’s Disease
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This disease has an unusual inheritance pattern for a
genetic disorder. It is caused by an autosomal
dominant gene.
What this means is that any person that develops
Huntington’s disease will have a parent that has had
this disorder.
h
H
Hh X hh
h
Hh
hh
h
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Hh
hh
All children of a person with Huntington’s have a 50%
chance of developing this disorder.
Prenatal testing
Amniocentesis
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This procedure involves the insertion of a
long needle into the woman’s abdomen
and the removal of a small amount of
amniotic fluid (about 2 teaspoons).
This test is done after the 15th week of
pregnancy and the location of the fetus
is monitored with ultrasound.
This is a relatively safe test, but does
carry about a 1 in 200 risk of
miscarriage.
The test is not done on all pregnant
women – only those that carry a higher
risk of genetic abnormalities (those with
genetic disorders in their family history
or women over 35).
Amniocentesis
Prenatal testing
Chorionic Villi Sampling
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This procedure is done between
the 10th and 12th week of
pregnancy and involves the
removal of a small amount of
the placenta.
This can be done either with the
insertion of a needle through the
abdomen or with a catheter
inserted through the vagina and
cervix.
There is a slightly higher risk of
miscarriage with this procedure
than with amniocentesis.
CVS
Many disorders that can be determined with prenatal testing.
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Achondroplasia
Huntington disease
Cystic fibrosis
Sickle cell disease
Tay-Sachs disease
Beta-thalassemia
Chromosomal disorders such as Down’s syndrome
Spina bifida
Anencephaly