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lines would you expect to be present in the
newborn?
(A)
46,XX and 47,XXX
(B)
45,X and 46,XX
(C)
45,X and 47,XXX
(D)
45,X, 46,XX and 47,XXX
125.
Bloom syndrome is an autosomal
recessive disorder that is associated with a
high frequency of spontaneous chromo-
some breakage due to a defect in a gene
involved in DNA replication. There is an
increased risk of malignancy associated
with this syndrome. The most likely expla-
nation for this observation is which one of
the following?
(A)
The mutated gene involved is a pro-
moter.
(B)
It is more likely that a chromosome
rearrangement may occur that will acti-
vate a proto-oncogene.
(C)
The mutation involved is a frame shift
mutation.
(D)
There is less cell death (apoptosis) with
this syndrome.
Questions 126 and 127 are based on the follow-
ing family history.
Mr. Z is a 20-year-old man found to have
thousands of polyps lining the entire colon.
In-vitro synthesized protein assay (IVSP)
confirms that the man has a mutation in the
APC gene responsible for familial adenoma-
tous polyposis (FAP). His father died of colon
cancer at age 40. Mr. Z has a 12-year-old
sister, Miss Z.
126.
What is the best plan of care for
Miss Z?
(A)
colectomy
(B)
test Miss Z with the IVSP assay to see if
she inherited an APC mutation
(C)
sigmoidoscopy every 3 months
(D)
do nothing besides routine well-child
visits
127.
Mr. Z’s wife is pregnant. What is the
chance that his child will inherit the muta-
tion responsible for FAP?
(A)
0%
(B)
25%
(C)
50%
(D)
100%
128.
Which one of the following applies to
classic phenylketonuria (PKU)?
(A)
It is a very rare disease in Caucasians.
(B)
It can be treated by limiting phenylala-
nine intake.
(C)
It causes disease only in childhood.
(D)
It does not affect the brain.
129.
Fluorescent in situ hybridization (FISH)
is often used to monitor patients with
chronic myelogenous leukemia (CML) for
minimal residual disease (MRD) after treat-
ment. The abl oncogene DNA probe is
labeled with a red fluorescent molecule and
the bcr gene probe is labeled with a green.
The bcr/abl fusion gene appears yellow
under UV light. Although metaphases are
usually available for FISH analysis, inter-
phases may give a better indication of MRD.
You “score” a CML patient slide using inter-
phase FISH to detect MRD. Out of the 200
cells you examine, you find that 150 have
two green and two red signals and 50 have
one green, one red, and one yellow signal.
This result indicates which one of the fol-
lowing?
(A)
There is no sign of MRD.
(B)
The fusion product is not being pro-
duced.
(C)
At least 25% of the cells examined are
malignant.
(D)
The sample was not informative.
130.
A change in the nucleotide sequence of
a gene is which one of the following?
(A)
genomic imprinting
(B)
transcription
(C)
mutation
(D)
synthesis
131.
A couple, both of whom have a
diagnosis of achondroplastic dwarfism,
want to know what the risk is of having a
child with normal height (they would
like another child with dwarfism).
Achondroplastic dwarfism is autosomal
dominant and the homozygous dominant
genotype is lethal very early in development.
What is the risk of having a child of normal
height?
(A)
0%
(B)
33%
(C)
50%
(D)
100%
Comprehensive Examination
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Questions 132 and 133 are based on the follow-
ing pedigree.
132.
What is the risk that any child that Abby
may have will be a carrier of a cystic fibrosis
mutation?
(A)
0%
(B)
25%
(C)
50%
(D)
100%
133.
What is the chance that Abby’s
brothers are carriers of the cystic fibrosis
mutation?
(A)
0%
(B)
50%
Abby
Cystic fibrosis
This is the family pedigree of Abby who has cystic
fibrosis, an autosomal recessive disease.
P
P
(C)
67%
(D)
100%
134.
A 25-year-old mother of two is con-
cerned because her 6-year-old son is “slow.”
She tells you that the father is also slow, as
was his father. Neither one finished school,
although they both work. The child has no
outstanding physical findings. The mother
says the child resembles the father. Your
assessment of the child is that there is some
degree of mental retardation. Assuming that
the grandfather, father, and son have the
same genetic basis for their mental retarda-
tion, the pedigree for this family would indi-
cate which of the following?
(A)
autosomal recessive inheritance
(B)
autosomal dominant inheritance
(C)
X-linked recessive inheritance
(D)
multifactorial inheritance
135.
In the Pingelapese population of the
eastern Caroline Islands in the Pacific, a
severe ocular abnormality characterized by
total colorblindness, photophobia, and
cataract development is found in approxi-
mately 10% of the population. Inheritance is
autosomal recessive. In 1780, a typhoon
struck the island, killing most of the inhabi-
tants. The survivors included only nine males.
The general population incidence of this dis-
order is 1 in 100,000. The high incidence of
this disorder in the Pingelapese population is
most likely due to which of the following?
(A)
assortative mating
(B)
selection against heterozygotes
(C)
founder effect
(D)
eugenics
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217
Answers and Explanations
1. The answer is (C).
Diabetes and most cancers have a number of environmental and
genetic components that are involved in their causation. Marfan syndrome and neurofi-
bromatosis are autosomal dominant disorders, Klinefelter and Turner syndromes are
caused by aneuploidy of the sex chromosomes, and cystic fibrosis and sickle cell anemia
are autosomal recessive diseases.
2. The answer is (A).
Human papilloma viruses (HPV) have been implicated as the chief
cause of cervical cancer. BCR, BRCA1, and Rb1 are genes involved in the development of
various cancers.
3. The answer is (A).
There is a risk for Robertsonian Down syndrome with this transloca-
tion. All the other combinations would be lethal if Robertsonian trisomies resulted, spon-
taneously aborting very early in the embryonic period.
4. The answer is (C).
Carriers of balanced chromosome rearrangements, such as reciprocal
translocations, are at risk for having conceptions with unbalanced rearrangements that
can lead to miscarriage.
5. The answer is (B).
In Fragile X syndrome, the CGG triplet repeat is sometimes expanded
as it is passed on through carrier females and once it reaches 230 copies in an individual,
that individual is affected. Males can pass on a “premutation” with fewer copies and there
is no expansion when males pass it on. Females who carry expansions over 230 may be
affected due to skewed X inactivation.
6. The answer is (C).
In leukemia, remission is marked by the disappearance of the chromo-
some abnormality associated with the particular type of leukemia. The derivative chro-
mosome 22 (the Philadelphia chromosome) associated with CML disappears in remis-
sion.
7. The answer is (B).
An affected individual in the family is the ideal person to be tested
because the specific mutation being passed on in the family can be identified by testing
that individual. Other individuals in the family can then be tested for that specific muta-
tion with accuracy and a considerable reduction in the cost of testing. Lila is the only
affected individual in the family still living, so she is the ideal person in the family to be
tested.
8. The answer is (A).
BRCA mutations are inherited in an autosomal dominant manner and
confer a 50%–80% lifetime risk for breast cancer depending on the specific mutation
involved. Preventative options include monitoring by mammography. Risks of BRCA test-
ing include psychological distress for positive AND negative results (guilt for not having
the mutation) and this can change relationships between positive and negative members
of a family. Even with a negative result, women still have a 1 in 8 lifetime risk of breast
cancer from other causes.
9.
In hematological cancers, structural chromosome rearrangements such as translocations
activate proto-oncogenes by juxtaposing them.
10. The answer is (A).
FAP confers a 100% lifetime risk of colon cancer if the polyps that
develop into the cancer are not removed.
11. The answer is (C).
The BRCA1 and 2 mutations convey an approximate lifetime risk of
ovarian cancer of 40% and a 6% risk of breast cancer for males in the family.
12. The answer is (A).
The tandem mass spectroscopy test for PKU is inexpensive, accurate,
and reliable. PKU is serious but an effective treatment, diet, is available and there are
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numerous treatment centers. The screening tests for the other disorders are expensive,
treatment success varies, and resources for diagnosis and treatment are not always read-
ily available.
13. The answer is (B).
Autism is a component of a number of chromosome abnormalities,
including Fragile X syndrome, but is a multifactorial disorder with a low recurrence risk.
A link between autism and childhood vaccines or gluten in the diet has not been con-
vincingly established.
14. The answer is (A).
In hereditary cancer syndromes, the inheritance of a mutated gene is
the first “hit” in the sequence of events leading the development of the cancer so the risk
of second hits is increased, thus leading to the increased risk for bilateral or multiple
tumors.
15. The answer is (A).
Because a strong genetic component to a trait would have a concor-
dance approaching 1.0 in monozygotic twins and have a large difference between the
concordance of monozygotic and dizygotic twins, concordance that is almost equal
between monozygotic and dizygotic twins means that the environmental component is
stronger than the genetic component.
16. The answer is (A).
Type 2 diabetes is far more common than type 1 diabetes, it is multi-
factorial with both genetic and environmental components, and recurrence risk in fami-
lies is quite high. Concordance in monozygous twins is approximately 90%. There is a
strong environmental component that is diet related.
17. The answer is (C).
The risk of developing cancer in adenomatous polyposis coli is 100% if
polyps are not removed. If they are removed, the cancer can effectively be prevented.
Prevention is not as successful with BRCA mutations, and is not possible for Huntington
disease or cystic fibrosis.
18. The answer is (A).
All 50 states screen for PKU, galactosemia, and hypothyroidism. Other
screening tests offered in the United States vary from state to state.
19. The answer is (D).
In X-linked recessive disorders, the incidence of the disease is the inci-
dence of the mutated gene “q.” The frequency of carrier females is “2pq.” Because “q” is
so small, “p” is close to 1, so the frequency of carrier females is 2(1)(1/20,000)
2/20,0001/10,000.
20. The answer is (B).
Autism is a component of many chromosome abnormalities so cytoge-
netic testing should always be done when autism is diagnosed in a patient.
21. The answer is (D).
In genetic lethals, the disease gene cannot be passed on, so the pres-
ence of the gene in the population is entirely due to new mutations that recreate the dis-
ease gene.
22. The answer is (D).
Sickle cell disease is autosomal recessive, Huntington disease is auto-
somal dominant, Rett syndrome is X-linked dominant, and Duchenne muscular dystro-
phy and Fragile X syndrome are X-linked recessive.
23. The answer is (E).
Fragile X syndrome is due to expansion of a triplet repeat, CGG. Sickle
cell disease is autosomal recessive, Huntington disease is autosomal dominant, Rett syn-
drome is X-linked dominant, and Duchenne muscular dystrophy and Fragile X syndrome
are X-linked recessive.
24. The answer is (B).
Rett syndrome is generally lethal in males and is characterized by
mental retardation and characteristic hand movements in affected females, among other
findings. Mental retardation is associated with Fragile X syndrome, but inheritance is
autosomal recessive and mostly males are affected. Mental retardation is not associated
with Huntington disease, Duchenne muscular dystrophy, or sickle cell disease.
25. The answer is (C).
These findings are associated with the degeneration of muscle tissue
characteristic of Duchenne muscular dystrophy and are not associated with any of the
other conditions listed.
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26. The answer is (E).
Fragile X syndrome is the most common cause of inherited mental
retardation. Mental retardation is a finding in individuals with Rett syndrome. None of
the other disorders listed are associated with mental retardation.
27. The answer is (C).
The 22q11.2 deletion has a 50% chance of being passed on because
there is a 50% chance of a gamete receiving the maternal or paternal chromosome 22
during meiosis. Because Hillary’s father has a heart defect, it is likely that he also has the
22q11.2 microdeletion and passed it on to his daughter.
28. The answer is (C).
Chromosome abnormalities are often spontaneous in origin. In auto-
somal dominant and X-linked dominant disease, there would most likely be other
affected family members and in mitochondrial disease, all children of an affected mother
would be affected.
29. The answer is (D).
Cri-du-chat (5p-) syndrome is a cytogenetically visible deletion so
FISH is not necessary.
30. The answer is (D).
Although infants with Tay-Sachs disease show no symptoms initially,
they begin to display symptoms sometime around six months of age and steadily deterio-
rate until death at approximately 5 years of age. Managing phenylalanine intake is impor-
tant for pregnant women with PKU, carriers of sickle cell trait are generally asympto-
matic, and there are many cystic fibrosis mutations that are not included in the common
screening tests.
31. The answer is (A).
Empirical data (Table) shows that the recurrence risk for an isolated
sacral appendage in North Carolina with one sibling affected is 5%.
32. The answer is (C).
The risk to each pregnancy in an autosomal dominant disorder is 50%.
33. The answer is (A).
Because cystic fibrosis is an autosomal recessive disease, I-1 is an obli-
gate carrier.
34. The answer is (B).
For any pregnancy with an autosomal recessive disorder, there is a 1/4
chance of not being a carrier, a 1/2 chance of being a carrier, and a 1/4 chance of being
affected. Because II-2 does not have cystic fibrosis there is a 1/3 chance of the remaining
possibilities that she is not a carrier, but a 2/3 chance of the remaining possibilities that
she is.
35. The answer is (D).
For any pregnancy with an autosomal recessive disorder, there is a 1/4
chance of not being a carrier, a 1/2 chance of being a carrier, and a 1/4 chance of being
affected.
36. The answer is (D).
Ultrasonography is usually performed, other than “dating” at around
12 weeks, in the period from 15 to 18 weeks of gestation and is approximately 80% accu-
rate in detecting major structural abnormalities. The “banana sign” and the “lemon sign”
are associated with myelomeningocele.
37. The answer is (A).
CVS and amniocentesis are the definitive tests for the prenatal diagno-
sis of chromosome abnormalities. CVS has a higher risk for miscarriage than amniocen-
tesis, and amniotic fluid AFP can be assayed to rule out neural tube defects.
38. The answer is (D).
Because hemochromatosis is an autosomal recessive disease, the
mother is an obligate carrier.
39. The answer is (A).
The risk of a chromosome abnormality for women who will deliver at
age 35 is
1% and will increase every year until menopause. Prenatal diagnosis would be
indicated for a male fetus if there was a known X-linked disease in the family. Fourth and
fifth relatives are so distantly related that any risks associated with genetic disorders are
close to the population risk.
40. The answer is (A).
Because males cannot pass on an X chromosome to their sons, in an X-
linked dominant condition all the daughters would be affected because the father only
had the one X with the mutation to pass on.
Answers and Explanations
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