L7 Autosomal Recess Spring 2014

8/10/2019 L7 Autosomal Recess Spring 2014

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Autosomal recessive disorders

In affected child both paternal andmaternal alleles are mutant

Both parents are heterozygous for mutation

(carriers)

N M

N NN NM

M NM MM


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Cystic fibrosis

Gaucher disease

Phenylketonuria

Tay-Sachs disease

Thalassemia

Sickle cell anemia

Some autosomal recessivedisorders


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Typical pedigree showing autosomal recessiveinheritance

Males and females affected in equal proportions

Affected individuals usually in only a single generation

Parents can be related, i.e. consanguineous


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Pedigree in which parentalconsanguinity suggests autosomal

recessive inheritance


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Types of consanguineous matingoptional


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The probability of being a carrier in afamily with an autosomal recessive disease

Parents of the child with autosomal recessivedisease are obligatorycarriers


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N M

N NN NM

M NM MMM

aternal

g

amets

Paternal gamets

Risks in families with AR disease

All sibs

affected 1/4carrier (healthy) 1/2

healthy (not carrier) 1/4

Healthy sibs onlyCarrier 2/3

Not carrier 1/3


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A couple, whose first child died from infantile

Tay-Sachs disease (autosomal recessive

lethal condition with 100% penetrance), isexpecting a new baby. What is a probability

that the baby will also be affected with

Tay-Sachs disease?

Q


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A couple, whose first child died from infantile

Tay-Sachs disease (autosomal recessive

lethal condition with 100% penetrance), isexpecting a new baby. What is a probability

that the baby will also be affected with

Tay-Sachs disease?

A

Answer: 1/4 (25%)


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A couple, whose first child died frominfantile 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


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A couple, whose first child died frominfantile Tay-Sachs disease (autosomal


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%)


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A couple, whose first child died from infantileTay-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 ofTay-Sachs

mutation?

A

Answer: 1/2 (50%)


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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


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A couple, whose first child died from



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%)


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A 30-year-old woman is phenotypically

normal but had a brother who died from


recessive lethal condition with 100%penetrance). What is the probability that

this woman is a heterozygous carrier for

Tay-Sachs disease?

Q


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A 30-year-old woman is phenotypically

normal but had a brother who died from


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%)


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Cystic fibrosis (CF)


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CF is the most common autosomal recessive disorder in

persons of northern European heritageCF incidence is 1 in 3200 live birthscarrier frequency is 1 in 25

Less frequently CF occurs in other ethnic and racial

populations (1 in 15,000 of African-Americans, and 1 in31,000 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


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Cystic fibrosis is caused by mutations in CFTR gene

The CFTR gene encodes a protein called the cysticfibrosis transmembrane conductance regulator. Thisprotein functions as a channel across the membraneof cells that produce mucus, sweat, saliva, tears, anddigestive enzymes. The channel transports chlorideions 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, freelyflowing mucus. Mucus lubricates and protects thelining of the airways, digestive system, reproductivesystem, and other organs and tissues.

The CFTR protein also regulates the function ofchannels, controlling transport of sodium ions.

CFTRgene

More than 1000 CFTR mutations are knowndeltaF508 is the most common mutation in CF patients

of European descent


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CF pathogenesis

Mutation in CFTR gene

abnormal function ofCFTR channel

more viscous mucus

clogged airway tubes

blocked pancreaticducts


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Systems and organ affected :respiratory tract (inflammation and chronic infectionmost commonly with Staphylococcus aureus andPseudomonas aeruginosa)

exocrine pancreas (pancreatic insufficiency in thegreat majority of CF patients)intestine (malabsorbtion; meconium ileus in 15%-20%of CF newborns)male genital tract (azoospermia due to congenitalabsence of vas deference )hepatobiliary systemexocrine sweat glands (salty sweat)

Cystic fibrosis is complex multisystem disease


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Respiratory

A persistent cough that produces thick spit(sputum) and mucusWheezingBreathlessnessA decreased ability to exercise

Repeated lung infectionsInflamed nasal passages or a stuffy nose

Digestive

Foul-smelling, greasy stoolsPoor weight gain and growthIntestinal blockage, particularly in newborns(meconium ileus)Severe constipation

Signs and Symptoms


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95% of male CF patients are infertile due to CAVD

Congenital Absence of the Vas Deferens(CAVD)

CAVD occurs also in men without pulmonary orgastrointestinal manifestations of CF. These casesare also result of CFTR mutations, but the genotypesof these men include either one severe and one mild

CFTR mutations or two mild mutations


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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 newbornscreening*

Laboratory diagnosis of CF

*CF newborn screening has been implemented in most of the United StatesTrypsinogen is synthesized in the pancreas; in CF, its release into thecirculation appears to be enhanced by abnormal pancreatic duct secretions.Thus, IRT levels are elevated in cystic fibrosis.


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More exercises


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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 aheterozygous carrier of the disease gene?

A. 1/4

B. 1/3C. 1/2D. 2/3E. 3/4

Q


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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 aheterozygous carrier of the disease gene?

A. 1/4

B. 1/3C. 1/2D. 2/3E. 3/4

A

Q


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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%

A


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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%


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A married couple is screened to assess the risk

for Gaucher disease in their children. Theactivities of glucocerebrosidase in the sera ofthe mother and father are 45% and 55%,respectively, of the reference value. The couple

has one child. Which of the following is theprobability of the child possessing one or morealleles of the Gaucher mutation?

(A) 0

(B) 0.25(C) 0.5(D) 0.75(E) 1.0

USMLE step 1 sample questionsQ


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A married couple is screened to assess the risk

for Gaucher disease in their children. Theactivities of glucocerebrosidase in the sera ofthe mother and father are 45% and 55%,respectively, of the reference value. The couple

has one child. Which of the following is theprobability of the child possessing one or morealleles of the Gaucher mutation?

(A) 0

(B) 0.25(C) 0.5(D) 0.75(E) 1.0

USMLE step 1 sample questionsQ

Low activities of glucocerebrosidase inboth parents indicate that both are

carriers


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Family has a child with cystic fibrosis and twohealthy sibs

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

Q. What is the probability for bothhealthysibs to be carriers?

Any (each)versus both


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A family has a child with cystic fibrosisand 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 bothhealthysibs to be carriers?

Answer: 2/3 x 2/3 = 4/9 = 0.44

Any (each)versus both


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A


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Consider a woman who is a known heterozygous

carrier of a mutation that causes PKU(autosomal recessive). What is the probabilitythat her grandchild (shown in the pedigree asindividual A) is a heterozygous carrier of this

PKU-causing allele? A. 1/64B. 1/32C. 1/16

D. 1/8E. 1/4

A

Answer:( x ) = 1/4

Q


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Consider a woman who is a known heterozygouscarrier of a mutation that causes PKU

(autosomal recessive). What is the probabilitythat her two grandchildren (shown in thepedigree as individuals A and B) are bothheterozygous carriers of this PKU-causingallele?

A. 1/64

B. 1/32C. 1/16D. 1/8E. 1/4

Q

A


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Consider a woman who is a known heterozygouscarrier of a mutation that causes PKU

(autosomal recessive). What is the probabilitythat her two grandchildren (shown in thepedigree as individuals A and B) are bothheterozygous carriers of this PKU-causing

allele? A. 1/64B. 1/32C. 1/16

D. 1/8E. 1/4

A

Answer:( x ) x ( x ) = 1/16

NBME


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A couple seeks genetic counseling followingthe recent diagnosis of cystic fibrosis in

their youngest child. Their two olderchildren are healthy and have normal sweatchloride test results. Which of thefollowing is the likelihood that each of theunaffected children is a carrier of cysticfibrosis?

A. 1 in 2

B. 1 in 3C. 1 in 4D. 2 in 3E. 3 in 4

NBME

Q

NBME


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A couple seeks genetic counseling followingthe recent diagnosis of cystic fibrosis in

their youngest child. Their two olderchildren are healthy and have normal sweatchloride test results. Which of thefollowing is the likelihood that each of theunaffected children is a carrier of cysticfibrosis?

A. 1 in 2

B. 1 in 3C. 1 in 4D. 2 in 3E. 3 in 4

NBME

A


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A 50-year-old man who has had a myocardial

infarct was subsequently diagnosed as havingfamilial hypercholesterolemia, an autosomaldominant disorder. His son has not been testedfor 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%

NBMEQ

NM

?

?

A


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A 50-year-old man who has had a myocardial

infarct was subsequently diagnosed as havingfamilial hypercholesterolemia, an autosomaldominant disorder. His son has not been testedfor 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%

NBMEA

probability that a proband

transmits to his sonx

probability that the sontransmits to his child =

0.5 x 0.5

loptional


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II-1II-2

II-3II-4II-5II-6

II-7

III-1III-2III-3III-4III-5III-6III-7

III-8III-9

I-1

I-2

What is the probability of being a carrier for eachmember of the family with a rare autosomal

recessive disease shown below ?


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II-1: 0*

II-2: affected

II-3: 2/3

II-40*

II-5 2/3II-6 2/3

II-7: 0*

III-1: 1

III-2: 1III-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:

optional


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The above pedigree illustrates four of the five hallmarks of autosomal recessive inheritance. I-1 andI-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

http://www.uic.edu/classes/bms/bms655/lesson5.html

L7 Autosomal Recess Spring 2014

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