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Lecture 6A

Autosomal recessive disorders


Autosomal recessive disorders
In affected child both paternal and
maternal alleles are mutant

Both parents are heterozygous for mutation
(carriers)
N M
N NN NM
M NM MM
Cystic fibrosis
Gaucher disease
Phenylketonuria
Tay-Sachs disease
Thalassemia
Sickle cell anemia
Some autosomal recessive
disorders
Typical pedigree showing autosomal recessive
inheritance
Males and females affected in equal proportions
Affected individuals usually in only a single generation
Parents can be related, i.e. consanguineous
Pedigree in which parental
consanguinity suggests autosomal
recessive inheritance
Types of consanguineous mating
optional
The probability of being a carrier in a
family with an autosomal recessive disease
Parents of the child with autosomal recessive
disease are obligatory carriers
N M
N NN NM
M NM MM
M
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Paternal gamets
Risks in families with AR disease
All sibs
affected 1/4
carrier (healthy) 1/2
healthy (not carrier) 1/4
Healthy sibs only
Carrier 2/3
Not carrier 1/3
A couple, whose first child died from infantile
Tay-Sachs disease (autosomal recessive
lethal condition with 100% penetrance), is
expecting a new baby. What is a probability
that the baby will also be affected with
Tay-Sachs disease?
Q
A couple, whose first child died from infantile
Tay-Sachs disease (autosomal recessive
lethal condition with 100% penetrance), is
expecting a new baby. What is a probability
that the baby will also be affected with
Tay-Sachs disease?
A
Answer: 1/4 (25%)
A couple, whose first child died from
infantile Tay-Sachs disease (autosomal
recessive lethal condition with 100%
penetrance), is expecting a new baby. What
is a probability that the baby will not be
affected with Tay-Sachs disease?
Q
A couple, whose first child died from
infantile Tay-Sachs disease (autosomal
recessive lethal condition with 100%
penetrance), is expecting a new baby. What
is a probability that the baby will not be
affected with Tay-Sachs disease?
A
Answer: 3/4 (75%)
A couple, whose first child died from infantile
Tay-Sachs disease (autosomal recessive lethal
condition with 100% penetrance), is expecting
a new baby. What is a probability that the
baby will be a carrier of Tay-Sachs
mutation?
Q
A couple, whose first child died from infantile
Tay-Sachs disease (autosomal recessive lethal
condition with 100% penetrance), is expecting
a new baby. What is a probability that the
baby will be a carrier of Tay-Sachs
mutation?
A
Answer: 1/2 (50%)
A couple, whose first child died from
infantile Tay-Sachs disease (autosomal
recessive lethal condition with 100%
penetrance), is expecting a new baby.
What is a probability that the baby will
be healthy and not carry a Tay-Sachs
mutation?
Q
A couple, whose first child died from
infantile Tay-Sachs disease (autosomal
recessive lethal condition with 100%
penetrance), is expecting a new baby.
What is a probability that the baby will
be healthy and not carry a Tay-Sachs
mutation?
A
Answer: 1/4 (25%)
A 30-year-old woman is phenotypically
normal but had a brother who died from
infantile Tay-Sachs disease (autosomal
recessive lethal condition with 100%
penetrance). What is the probability that
this woman is a heterozygous carrier for
Tay-Sachs disease?
Q
A 30-year-old woman is phenotypically
normal but had a brother who died from
infantile Tay-Sachs disease (autosomal
recessive lethal condition with 100%
penetrance). What is the probability that
this woman is a heterozygous carrier for
Tay-Sachs disease?
A
Answer: 2/3 (66%)
Cystic fibrosis (CF)
CF is the most common autosomal recessive disorder in
persons of northern European heritage
CF incidence is 1 in 3200 live births
carrier frequency is 1 in 25
Less frequently CF occurs in other ethnic and racial
populations (1 in 15,000 of African-Americans, and 1 in
31,000 Asian Americans)
Approximately 30,000 CF patients live in the US
Previously CF was considered as a fatal disorder,
currently, due to the progress in treatment, as a time-
limiting (median survival is 37 years)
CF Prevalence
Cystic fibrosis is caused by mutations in CFTR gene
The CFTR gene encodes a protein called the cystic
fibrosis transmembrane conductance regulator. This
protein functions as a channel across the membrane
of cells that produce mucus, sweat, saliva, tears, and
digestive enzymes. The channel transports chloride
ions into and out of cells. The transport of chloride
ions helps control the movement of water in tissues,
which is necessary for the production of thin, freely
flowing mucus. Mucus lubricates and protects the
lining of the airways, digestive system, reproductive
system, and other organs and tissues.
The CFTR protein also regulates the function of
channels, controlling transport of sodium ions.
CFTR gene
More than 1000 CFTR mutations are known
deltaF508 is the most common mutation in CF patients
of European descent
CF pathogenesis
Mutation in CFTR gene

abnormal function of
CFTR channel

more viscous mucus

clogged airway tubes
blocked pancreatic
ducts
Systems and organ affected :
respiratory tract (inflammation and chronic infection
most commonly with Staphylococcus aureus and
Pseudomonas aeruginosa)
exocrine pancreas (pancreatic insufficiency in the
great majority of CF patients)
intestine (malabsorbtion; meconium ileus in 15%-20%
of CF newborns)
male genital tract (azoospermia due to congenital
absence of vas deference )
hepatobiliary system
exocrine sweat glands (salty sweat)
Cystic fibrosis is complex multisystem disease
Respiratory
A persistent cough that produces thick spit
(sputum) and mucus
Wheezing
Breathlessness
A decreased ability to exercise
Repeated lung infections
Inflamed nasal passages or a stuffy nose

Digestive
Foul-smelling, greasy stools
Poor weight gain and growth
Intestinal blockage, particularly in newborns
(meconium ileus)
Severe constipation
Signs and Symptoms
95% of male CF patients are infertile due to CAVD
Congenital Absence of the Vas Deferens
(CAVD)
CAVD occurs also in men without pulmonary or
gastrointestinal manifestations of CF. These cases
are also result of CFTR mutations, but the genotypes
of these men include either one severe and one mild
CFTR mutations or two mild mutations
Presence of two disease-causing mutations in CFTR
Two abnormal sweat chloride tests (>60 mEq/L)
Transepithelial nasal potential difference (NPD)
measurements characteristic of CF
immunoreactive trypsinogen (IRT) assays in newborn
screening*
Laboratory diagnosis of CF
*CF newborn screening has been implemented in most of the United States
Trypsinogen is synthesized in the pancreas; in CF, its release into the
circulation appears to be enhanced by abnormal pancreatic duct secretions.
Thus, IRT levels are elevated in cystic fibrosis.
More exercises
A woman who has normal skin pigmentation has
two sisters with oculocutaneous albinism, a fully
penetrant autosomal recessive disease. What
is the probability that this woman is a
heterozygous carrier of the disease gene?
A. 1/4
B. 1/3
C. 1/2
D. 2/3
E. 3/4
Q
A woman who has normal skin pigmentation has
two sisters with oculocutaneous albinism, a fully
penetrant autosomal recessive disease. What
is the probability that this woman is a
heterozygous carrier of the disease gene?
A. 1/4
B. 1/3
C. 1/2
D. 2/3
E. 3/4
A
The accompanying pedigree shows two
individuals who are affected with tyrosinase-
negative albinism (autosomal recessive). What
is the risk that their grandchild will be
affected with this disorder?
Q
A. 25%
B. 50%
C. 75%
D. 100%
The accompanying pedigree shows two
individuals who are affected with tyrosinase-
negative albinism (autosomal recessive). What
is the risk that their grandchild will be
affected with this disorder?
A
A. 25%
B. 50%
C. 75%
D. 100%
Each grandparent has two mutant allele therefore both parents
are carriers. The chance of affected child in two carriers is 25%
A married couple is screened to assess the risk
for Gaucher disease in their children. The
activities of glucocerebrosidase in the sera of
the mother and father are 45% and 55%,
respectively, of the reference value. The couple
has one child. Which of the following is the
probability of the child possessing one or more
alleles of the Gaucher mutation?
(A) 0
(B) 0.25
(C) 0.5
(D) 0.75
(E) 1.0
USMLE step 1 sample questions
Q
A married couple is screened to assess the risk
for Gaucher disease in their children. The
activities of glucocerebrosidase in the sera of
the mother and father are 45% and 55%,
respectively, of the reference value. The couple
has one child. Which of the following is the
probability of the child possessing one or more
alleles of the Gaucher mutation?
(A) 0
(B) 0.25
(C) 0.5
(D) 0.75
(E) 1.0
USMLE step 1 sample questions
Q
Low activities of glucocerebrosidase in
both parents indicate that both are
carriers
Family has a child with cystic fibrosis and two
healthy sibs

Q. What is the probability for any (each)
healthy child to be a carrier?


Q. What is the probability for both healthy
sibs to be carriers?

Any (each) versus both
A family has a child with cystic fibrosis
and two healthy sibs

Q. What is the probability for any (each)
healthy child to be a carrier?

Answer: 2/3 = 0.66

Q. What is the probability for both healthy
sibs to be carriers?
Answer: 2/3 x 2/3 = 4/9 = 0.44

Any (each) versus both
Consider a woman who is a known heterozygous
carrier of a mutation that causes PKU
(autosomal recessive). What is the probability
that her grandchild (shown in the pedigree as
individual A) is a heterozygous carrier of this
PKU-causing allele?
A. 1/64
B. 1/32
C. 1/16
D. 1/8
E. 1/4
Q
Consider a woman who is a known heterozygous
carrier of a mutation that causes PKU
(autosomal recessive). What is the probability
that her grandchild (shown in the pedigree as
individual A) is a heterozygous carrier of this
PKU-causing allele?
A. 1/64
B. 1/32
C. 1/16
D. 1/8
E. 1/4
A
Answer:
( x ) = 1/4
Consider a woman who is a known heterozygous
carrier of a mutation that causes PKU
(autosomal recessive). What is the probability
that her two grandchildren (shown in the
pedigree as individuals A and B) are both
heterozygous carriers of this PKU-causing
allele?
A. 1/64
B. 1/32
C. 1/16
D. 1/8
E. 1/4
Q
Consider a woman who is a known heterozygous
carrier of a mutation that causes PKU
(autosomal recessive). What is the probability
that her two grandchildren (shown in the
pedigree as individuals A and B) are both
heterozygous carriers of this PKU-causing
allele?
A. 1/64
B. 1/32
C. 1/16
D. 1/8
E. 1/4
A
Answer:
( x ) x ( x ) = 1/16
A couple seeks genetic counseling following
the recent diagnosis of cystic fibrosis in
their youngest child. Their two older
children are healthy and have normal sweat
chloride test results. Which of the
following is the likelihood that each of the
unaffected children is a carrier of cystic
fibrosis?
A. 1 in 2
B. 1 in 3
C. 1 in 4
D. 2 in 3
E. 3 in 4
NBME
Q
A couple seeks genetic counseling following
the recent diagnosis of cystic fibrosis in
their youngest child. Their two older
children are healthy and have normal sweat
chloride test results. Which of the
following is the likelihood that each of the
unaffected children is a carrier of cystic
fibrosis?
A. 1 in 2
B. 1 in 3
C. 1 in 4
D. 2 in 3
E. 3 in 4
NBME
A
A 50-year-old man who has had a myocardial
infarct was subsequently diagnosed as having
familial hypercholesterolemia, an autosomal
dominant disorder. His son has not been tested
for hypercholesterolemia. What is the
probability that the patient's granddaughter,
through his son, will have hypercholesterolemia?
A. Less than 1%
B. 10%
C. 25%
D. 33%
E. 50%
NBME Q
NM
?
?
A 50-year-old man who has had a myocardial
infarct was subsequently diagnosed as having
familial hypercholesterolemia, an autosomal
dominant disorder. His son has not been tested
for hypercholesterolemia. What is the
probability that the patient's granddaughter,
through his son, will have hypercholesterolemia?
A. Less than 1%
B. 10%
C. 25%
D. 33%
E. 50%
NBME
A
probability that a proband
transmits to his son
x
probability that the son
transmits to his child =
0.5 x 0.5
II-1
II-2
II-3
II-4
II-5
II-6
II-7
III-1
III-2
III-3
III-4
III-5
III-6
III-7
III-8
III-9
I-1
I-2
What is the probability of being a carrier for each
member of the family with a rare autosomal
recessive disease shown below ?
optional
II-1: 0*
II-2: affected
II-3: 2/3
II-4 0*
II-5 2/3
II-6 2/3
II-7: 0*
III-1: 1
III-2: 1
III-3: 1
III-4: 1/3
III-5: 1/3
III-6: 1/3
III-7: 1/3
III-8: 1/3
III-9: 1/3
I-1: 1
I-2: 1
Answer:
The above pedigree illustrates four of the five hallmarks of autosomal recessive inheritance. I-1 and
I-2 are unrelated, yet they produced an affected offspring (affected offspring have normal parents).
By chance, they both must have been carriers. Even though II-2 is affected, she produced no
affected offspring (trait appears in siblings, not parents or offspring). By far the most probable
genotype for an individual from outside the family (II-1) is homozygous normal. III-1, III-2 and III-3
are all obligate carriers (heterozygotes), since they are not affected but could only have inherited
the recessive gene from II-2. The II-3, II-5, and II-6 each have a 2/3 chance of being a carrier and a
1/3 chance of being homozygous normal. They are not affected, but they come from a carrier x
carrier mating. II-4 and II-7 have a high probability of being homozygous normal since they are from
outside the family. III-4, III-5, III-6, III-7, III-8, and III-9 all have a 1/3 chance of being carriers and a
2/3 chance of being homozygous normal. One parent of each is probably homozygous normal, the
other has a 2/3 chance of being a carrier and a 1 in 2 chance of passing on the recessive allele if they
were a carrier
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