The wife of a 48-year-old male patient brings him to the emergency room and says that his memory

has progressively gotten worse over the last several years. She also says his personality has
been changing. The physician notes abnormal writhing movements of the man's limbs and
hyperreactive reflexes. MRI reveals a loss of volume in the neostriatum and cortex. This disease
is inherited via an

A. autosomal dominant trait

B. autosomal recessive trait

C. x-linked dominant trait

D. x-linked recessive trait

Explanation:

The correct answer is A. This patient has Huntington's disease, which has autosomal dominant
inheritance. It is characterized by severe degeneration of the caudate nucleus along with
degenerative changes in the putamen and cortex. In addition to chorea, these patients frequently
suffer from athetoid (writhing) movements, progressive dementia, and behavioral disorders.

Genotype Enzyme Activity Phenotype G/G 100 Normal G/D 75 Normal G/LA 120 Normal G/g 50
Normal
D/D 50 Normal D/LA 95 Normal LA/LA 140 Normal LA/g 70 Normal g/g <5 Galactosemia

Galactosemia, an inability to metabolize galactose, results from a deficiency of the enzyme

galactose-1-phosphate uridyltransferase. The table above summarizes the genotypes and phenotypes
at this locus. Which of the following alleles show less than normal activity of the enzyme?

A. D and G

B. D and g

C. D and LA

D. D only

E. G and g

F. G and LA

G. G only

H. g and LA

I. g only

Explanation:

The correct answer is B. While the phenotype for D/D is normal, the enzyme activity is
decreased. For g/g, the phenotype is affected and the enzyme activity is negligible. If you also
look at the enzyme activity levels for heterozygotes such as G/g and G/D, their enzyme activity
is diminished, even though their phenotype is normal. LA is an allele with enhanced enzyme
activity and the heterozygote LA/D shows almost wild-type enzyme activity. Only the D allele and
g allele are consistently associated with decreased enzyme activity.
Tissue from a spontaneous abortion is submitted to the laboratory, where an astute pathologist
notes the presence of mature fetal tissue that contains Barr bodies. The fetus may have had
which of the following genotypes?

A. Classic Turner syndrome (45, X)

B. Edward's syndrome (47, XY+18)

C. Klinefelter's syndrome (47, XXY)

D. Normal male (46, XY)

E. XYY syndrome (47, XYY)

Explanation:

The correct answer is C. The Barr body, or X chromatin body, is an inactivated X chromosome seen
as a small, perinuclear, dark-staining dot in somatic cells with two or more X chromosomes. Barr
bodies are seen in any individual born with at least two X chromosomes, including normal
females. (47, XXY), the classic karyotype of Klinefelter's syndrome, is defined as male
hypogonadism due to the presence of a Y chromosome and two or more X's. As in normal females,
one of the X chromosomes becomes a Barr body in Klinefelter's syndrome.

Classic Turner syndrome females (choice A) and genotypically normal males (choice D) have only
one X chromosome. Thus, no X chromosome is inactivated, and somatic cells do not show any Barr
bodies.

(47, XY+18) is the karyotype of an Edward's syndrome (choice B) fetus. Although this trisomic
phenotype is associated with a characteristic syndrome of physical abnormalities, there is no
programmed inactivation of the extra chromosome 18. Thus, no Barr body is produced.

XYY syndrome (choice E) is not associated with inactivation of any X chromosomes, so Barr bodies
are not present. Like a trisomy involving any of the non-sex-linked chromosomes, the duplicated
chromosome is expressed in its entirety.

Karyotypic analysis of a spontaneously aborted fetus demonstrates trisomy of one of the

chromosomes. Which chromosome is most likely to be affected?

A. 8

B. 13

C. 16

D. 18

E. 21

Explanation:

The correct answer is C. Approximately half of all spontaneous abortions are of fetuses with
major chromosomal defects, most commonly trisomy 16, triploidy (due to fertilization of an egg
by two sperm), and 45 X,0 (Turner's syndrome). Trisomy 16 and triploidy do not produce viable
offspring, unlike 45 X,0.
Trisomy 8 (choice A) is one of the very rare causes of live birth trisomies.

Trisomy 13 (choice B) is one of the more common live birth trisomy syndromes (Patau syndrome).

Trisomy 18 (choice D) is one of the more common live birth trisomy syndromes (Edwards' syndrome)

Trisomy 21 (choice E) causes Down's syndrome.

On physical examination, a newborn is found to have micrognathia, a prominent occiput, low-set

ears, and rocker-bottom feet. There is very little mental development during the first months of
life and the infant dies of cardiac complications after 8 months. A complete karyotype of this
child would yield which of the following?

A. XO

B. XXY

C. Trisomy 13

D. Trisomy 18

E. Trisomy 21

Explanation:

The correct choice is D. This chromosomal aberration is also known as Edwards' syndrome, or
trisomy 18. It is characterized by mental deficiency, growth retardation, prominent occiput,
micrognathia, low-set ears, rocker-bottom feet, and ventricular septal defect.

XO (choice A) is the karyotype of Turner syndrome. It is characterized by short stature, webbed

neck, and hypogonadism.

XXY (choice B) represents Klinefelter syndrome. It is usually undetected at birth but is

characterized by tall stature, male hypogonadism, and sometimes, mental retardation.

Trisomy 13 (Patau syndrome; choice C) is characterized by mental retardation, nervous system

malformations, rocker-bottom feet, polydactyly, and cleft lip and palate.

Trisomy 21 (Down syndrome; choice E) is characterized by mental retardation, protruding tongue,

simian crease, congenital heart defects, and a flat nasal bridge.

A 15-year-old boy is evaluated by a clinician for failure to develop normal male secondary
sexual characteristics. Physical examination reveals small testes, a small penis, and
gynecomastia. The boy has had some difficulties in school, and the parents say that the school
psychometrist said he had an IQ of 90. This patient's condition is most likely to be related to
which of the following?

A. Deletion

B. Nondisjunction of an autosomal chromosome

C. Nondisjunction of a sex chromosome

D. Non-Robertsonian translocation

E. Robertsonian translocation
Explanation:

The correct answer is C. The boy probably has Klinefelter's syndrome (47, XXY), which has the
typical presentation described in the question. The condition arises as a result of failure of
separation (nondisjunction) of the sex chromosomes, and can be related to either paternal
nondisjunction (slightly more common) or maternal nondisjunction.

Deletions (choice A) are a common form of genetic disease and contribute to many genetic
recessive diseases.

Examples of nondisjunction of autosomes (choice B) include trisomies such as most cases of

Down's syndrome (trisomy 21), Edwards' syndrome (trisomy 18), and Patau syndrome (trisomy 13).

There are two types of translocations: non-Robertsonian (choice D) and Robertsonian (choice E).
Non-Robertsonian (reciprocal) translocations result when two non-homologous chromosomes
exchange
genetic material. Robertsonian translocations are a special type of translocation that involve
exchange of genetic material from the long arms of one acrocentric chromosome to the long arms
of another acrocentric chromosome, with fusion of the centromeres. Four percent of cases of
Down's syndrome are caused by this mechanism.

A 20-year-old develops weakness accompanied by difficulty in relaxation that is most pronounced

in the hands and feet. Muscle biopsy demonstrates prominent ring fibers, centrally located
nuclei, chains of nuclei, and disorganized sarcoplasmic masses. This condition has been
associated with a mutation on which of the following chromosomes?

A. X

B. Y

C. 4

D. 5

E. 19

Explanation:

The correct answer is E. The disease is myotonic dystrophy, which is an autosomal dominant
disease; the affected gene has been localized to chromosome 19. Myotonic dystrophy is relatively
common and is best thought of as a systemic disease, since it causes cataracts, testicular
atrophy, heart disease, dementia, and baldness in addition to muscular weakness.

A mutation on the X chromosome (choice A) causes Duchenne muscular dystrophy.

None of the muscle diseases are known to be related to defects on the Y chromosome (choice B).

Facioscapulohumeral dystrophy is associated with a defective gene on chromosome 4 (choice C).

Infantile hypotonia has been related to defective genes on chromosome 5 (choice D).

Which of the following diseases has an X-linked recessive inheritance pattern?

A. Alpha1-antitrypsin deficiency
B. Cystic fibrosis

C. Duchenne muscular dystrophy

D. Phenylketonuria

E. Tay-Sachs disease

Explanation:

The correct answer is C. Duchenne-type muscular dystrophy is the only disease listed that is X-
linked; the other diseases are autosomal recessive. Remembering the genetics of myriads of
diseases is very problematic, but here are some imperfect rules of thumb that can help you out
if you encounter an unfamiliar disease on an examination. Deficiencies of most enzymes are
recessive (either autosomal or X-linked), since each person has at least two copies (from each
of the parents) of each enzyme, and one working gene is usually enough (although careful
evaluation of heterozygotes often shows mildly altered physiology). In contrast, alterations in
structural proteins are often autosomal dominant, since having any amount of abnormal protein in
structures such as basement membranes or in collagen tends to disturb their function. The number
of common X-linked diseases (almost all recessive) is small, and can be memorized: Duchenne
muscular dystrophy, hemophilia A and B, chronic granulomatous disease, glucose-6- phosphate
dehydrogenase deficiency, agammaglobulinemia, Wiskott-Aldrich syndrome, diabetes insipidus,
Lesch-Nyhan syndrome, fragile-X syndrome, and color blindness.

Alpha1-antitrypsin deficiency (choice A) is a deficiency of an enzyme (alpha1-antitrypsin) that

inhibits the action of various proteolytic enzymes. The two autosomal alleles for alpha1-
antitrypsin are codominantly expressed such that they both contribute to the levels of
circulating alpha1-antitrypsin.

Cystic fibrosis (choice B) is an autosomal recessive disorder. The gene for cystic fibrosis has
been localized to chromosome 7.

Phenylketonuria (choice D), in its classical form, is an autosomal recessive deficiency of

phenylalanine hydroxylase.

Tay-Sachs disease (choice E) is an autosomal recessive deficiency of the enzyme hexosaminidase

A.

Microscopic examination of a cancer cell reveals a cell in an abnormal telophase in which three
clusters of chromosomes are seen. An abnormality of which of the following would be most likely
to produce this alteration?

A. Chiasma

B. Mitotic spindle

C. Mosaicism

D. Polar body

E. Synapsis

Explanation:

The correct answer is B. Abnormal mitotic spindles can produce tripolar mitoses. These are
clearly abnormal mitoses that, when present, are considered definitive evidence that a tumor is
malignant rather than benign. They are therefore often searched for by pathologists evaluating a
tumor.

Chiasma (choice A) is the cross-like structure produced when a homologous pair of chromosomes
aligns to exchange genetic material.

Mosaicism (choice C) refers to a difference in genetic material in different somatic cells of

the same organism.

A polar body (choice D) is a daughter cell of a developing oocyte that contains almost no
cytoplasm.

Synapsis (choice E) is a formal name for the pairing of homologous chromosomes with which
meiosis begins.

A 28-year-old woman gives birth to a 1850 gm infant after a difficult pregnancy complicated by
oligohydramnios. The infant is placed in the neonatal intensive care unit and tissue from the
umbilical cord is sent for cytogenetic analysis. The infant's karyotype is 46, XY with no
apparent abnormalities. No biochemical abnormalities are detected. The observed intrauterine
growth retardation might have been caused by

A. chromosomal deletion

B. confined placental mosaicism

C. expansion of tandem nucleotide repeats

D. fetal trisomy

E. genomic imprinting

Explanation:

The correct answer is B. Confined placental mosaicism is the consequence of a genetic aberration
occurring in the trophoblast or in extraembryonic progenitor cells in the inner cell mass. The
genetic abnormality (e.g., a trisomy) leads to abnormal placental development and intrauterine
growth retardation. Since the genetic abnormality is present only in the placenta, no genetic
abnormalities will be detected in the neonate. Genetic mosaicism may also be confined to the
embryo, or may be constitutional (affecting both the embryo and the placenta), depending on when
the mutation occurs.

A chromosomal deletion (choice A) or fetal trisomy (choice D) are ruled out by the normal
karyotype.

Expansion of tandem nucleotide repeats (choice C) is thought to be involved in Fragile X

syndrome and Huntington disease. Cytogenetic testing would have revealed this abnormality.

Genomic imprinting (choice E) is the phenomenon in which the phenotypic expression of a gene
differs if the gene is inherited from the mother, as opposed to the father. Genomic imprinting
may affect expression of the genetic defect in confined placental mosaicism, but it is not the
cause of the observed intrauterine growth retardation.

An infant develops tetany on the second day of life. Physical examination is remarkable for
dysmorphic facies with low-set ears and micrognathia. Determination of serum electrolytes
reveals severe hypocalcemia. Which of the following chromosomal aberrations is most likely
responsible for this presentation?
A. Deletion in chromosome 22

B. Monosomy of chromosome 5

C. Translocation of chromosome 21

D. Trisomy of chromosome 13

E. Trisomy of X chromosome

Explanation:

The correct answer is A. DiGeorge syndrome is caused by malformation of the third and fourth
pharyngeal pouches, leading to absence of the thymus and parathyroid glands, among other
abnormalities. It was originally believed that DiGeorge syndrome was an acquired abnormality,
but recent studies suggest that deletions of chromosome 22q11 are frequently involved. Infants
afflicted with this syndrome present as dysmorphic babies who develop convulsions or tetany a
short time after birth due to severe hypocalcemia caused by a lack of parathyroid hormone. These
patients are very difficult to manage, and frequently have severe associated cardiac defects
that may lead to death. Survivors often have at least small amounts of residual thymic tissue,
and have a few circulating T cells that tend to slowly increase with age. Antibody production is
usually adequate.

A slightly mentally retarded individual with menstrual irregularities is found to have a 47, XXX
karyotype. The average life span for individuals with this condition is

A. 10-20 years

B. 20-30 years

C. 30-40 years

D. 40-50 years

E. normal

Explanation:

The correct answer is E. 47, XXX is a surprisingly benign condition, the incidence of which is
unknown because most cases are never diagnosed, as a normal phenotype with normal life span is
typical. There is some increase in the incidence of mental retardation and menstrual
irregularities in the population, particularly with increasing numbers of supernumerary X
chromosomes. Presumably, the inactivation of the extra X chromosome (forming a second Barr body
that may be observed on a buccal smear examined for other reasons) limits the expression of the
extra genes.

A cloned DNA fragment, when used as a probe, reveals a restriction fragment length polymorphism
(RFLP) in the region adjacent to the centromere of chromosome 21. Four haplotypes exist: A, B,
C, and D. An AB woman and a CD man have a child with trisomy 21 who is ACC. Nondisjunction
occurred in

A. the child during the first mitotic division

B. the father during meiosis I

C. the father during meiosis II

D. the mother during meiosis I

E. the mother during meiosis II

Explanation:

The correct answer is C. The RFLP detects a region near the centromere of chromosome 21. The
region around the centromere exhibits a phenomenon called crossover suppression. Since genetic
exchange cannot happen in this area, the probe is a reliable marker for the individual
chromosomes. During meiosis II, sister chromatids, which are two identical copies of the same
chromosome, should separate. If a nondisjunction event occurs in this division, two copies of
the same chromosome are passed to the progeny. In this case, both parents are heterozygous for
the probe. The child received an A from the mother and two Cs from the father, leading us to
conclude that the problem occurred in the father during meiosis II.

Choice A (the child during the first mitotic division). If a nondisjunction event of chromosome
21 occurs early in development, a child that is a mosaic for trisomy 21 is the result. This
accounts for approximately 1% of children with trisomy 21. Since some of their cells are normal,
these individuals show only a mild expression of the trisomy 21 phenotype.

Choice B (the father during meiosis I). During meiosis I, homologues that carry similar but not
identical information separate. If a failure occurred in this division, we would expect the man
to pass CD and the woman to pass A or B, producing a child that was ACD or BCD.

Choice D (the mother during meiosis I). If an AB woman had a failure in meiosis I, an AB gamete
would be produced. When fertilized by the man's C or D sperm, a child that was ABC or ABD would
result.

Choice E (the mother during meiosis II). If an AB woman's sister chromatids failed to disjoin
during meiosis II, AA or BB gametes would result. When fertilized by the CD male's sperm, a
child that was AAC, AAD, BBC, or BBD would result.

Examination of a karyotype taken from a metaphase preparation reveals the presence of an extra
chromosome. Which of the following is the most common mechanism of producing this phenomenon?

A. Balanced translocation

B. Chromosomal breakage

C. Fertilization by two sperm

D. Nondisjunction

E. Unbalanced translocation

Explanation:

The correct answer is D. Nondisjunction can occur in both meiosis and mitosis, and refers to a
failure of paired chromosomes to separate and go to different daughter cells. When this happens,
one daughter cell gets an extra chromosome and the other daughter cell is "short" one
chromosome.

A balanced translocation (choice A) is an exchange of genetic material between non-homologous

chromosomes that preserves all critical genetic material.
Chromosomal breakage (choice B) produces fragmented chromosomes and can contribute to
tumorigenesis.

Fertilization by two sperm (choice C) produces triploidy and is seen in many spontaneously
aborted fetuses.

An unbalanced translocation (choice E) occurs when non-homologous chromosomes exchange

genetic
material with a net loss or gain of critical genetic material.

A 13-year-old boy is brought to a rural clinic because of poor school performance. His parents
state that he did not begin talking until after three years of age, and still does not use
language as effectively as his sister, who is 6-years-old. A careful family history reveals that
a maternal grandfather was mildly retarded. The mother has two sisters, both of whom are
apparently normal, but the mother admits that she did not do well in school, and dropped out at
the age of 16. Physical examination of the child reveals large ears, a long, narrow face, and
large testes. Which of the following genetic mechanisms most likely accounts for the observed
findings in the son?

A. Expanded trinucleotide repeat

B. Genomic imprinting

C. Robertsonian translocation

D. Trisomy 13

E. Trisomy 18

Explanation:

The correct answer is A. The features described are typical of the familial form of mental
retardation known as fragile X syndrome. This disorder is the second most common heritable cause
of mental retardation, second only to Down syndrome. Striking features of this disease are that
the clinical features tend to worsen with each successive generation, and that males are usually
much more severely affected than females, although nearly 50% of carrier females are at least
slightly mentally retarded. The explanation appears to involve a region of DNA on the X
chromosome that normally contains 6-54 tandem repeats of the sequence CGG. Carrier females for
fragile X syndrome may have up to 200 CGG repeats. Clinically affected individuals have
250-4,000 repeats of the CGG sequence. The greater the number of repeats, the more severe the
retardation tends to be. Amplification of premutations to full mutations appears much more
likely to occur during oogenesis than spermatogenesis.

Genomic imprinting (choice B) is a phenomenon in which the phenotypic expression of a gene

differs if the gene is inherited from the mother, rather than the father. An example of this
effect is Angelman ("happy puppet") syndrome, caused by a deletion of band q12 in the maternal
copy of chromosome 15. A similar deletion in the paternal chromosome 15 produces a different
disease called Prader-Willi syndrome.

A Robertsonian translocation (choice C) causes about 5% of cases of Down syndrome. Generally the
mother [typically with genotype 45, XX, -14, -21, +t(14q; 21q)] has normal mentation, but some
of her children may carry the translocation in addition to the normal maternal chromosome 21 and
normal paternal chromosome 21, producing partial trisomy 21. This form of Down syndrome can
appear to be a recessive genetic disease.
Trisomy 13 (Patau syndrome; choice D) is characterized by microcephaly, mental retardation,
cleft lip and palate, polydactyly, and rocker-bottom feet. Survival is rare beyond one year.

Trisomy 18 (Edwards syndrome; choice E) is characterized by mental retardation, micrognathia,

low-set ears, cardiac defects, renal defects, and rocker-bottom feet. Survival is rare beyond
one year.

In a certain population, the frequency of color-blind males is 1 in 100. Assuming that the
population is in Hardy-Weinberg equilibrium at this locus, the frequency of color-blind females
is approximately

A. 0.0001

B. 0.0005

C. 0.01

D. 0.02

E. 0.025

Explanation:

The correct answer is A. Color blindness is an X-linked recessive trait. A male is hemizygous
for the X chromosome, and thus has only one copy of each trait. The frequency of an X-linked
recessive in males is thus equal to the frequency of the allele in the population. From this, we
know that q = 0.01 and p = 0.99. A female has two copies of each gene on the X chromosome, so
the equation for Hardy-Weinberg equilibrium is the same as for the autosomal traits. In this
case, a homozygous recessive female would occur at a frequency of q2 or 0.0001.

Choice B, 0.0005, is incorrect. If you remembered that color blindness was more frequent in
males, but did not know how to use the equations to get the true estimate, you might have
guessed this answer.

Choice C, 0.01, makes the assumption that the trait is autosomal, and so the frequencies of
affected males and affected females are equal.

Choice D, 0.02, assumes that q = 0.01, and then calculates the frequency of carrier females
(2pq).

Choice E, 0.025 is also incorrect; it is a distracter.

A 3 year-old boy is brought to a physician because the mother notices that the child is engaging
in less active play and tires easily. During physical examination, the pediatrician notices that
the child's thighs are larger than normal for age and that the child cannot stand up without
using his arms to help. Further studies demonstrate a defective dystrophin gene in the boy.
Which of the following people in the child's family is most likely to also have this disease?

A. Father

B. Father's brother

C. Mother

D. Mother's brother
E. Sister

Explanation:

The correct answer is D. The disease is Duchenne muscular dystrophy, an X-linked recessive
muscular disease usually caused by a deletion involving the dystrophin gene. This defect
produces accelerated muscle breakdown leading initially to proximal muscle weakness, then later
to generalized weakness that typically begins before age 5. A feature of X-linked recessive
diseases is that carrier mothers pass the disease to half their sons; affected fathers can have
carrier daughters but not affected sons. Since the mother is presumably normal (because the
disease is X-linked), she must be a carrier to have an affected son, and the grandmother must
also be a carrier, therefore the mother's brother (maternal uncle) may also have the disease.

The father's (choice A) side of the family, including the father's brother (choice B), most
likely does not carry the defective gene (since they themselves would be affected, and
furthermore since the father cannot pass the gene on to a son). It would be extremely unlikely
for a carrier female to marry an affected male (and the question does not mention any similar
symptoms in the father).

The mother (choice C) and possibly the sister (choice E) are carriers of, but not affected by,
the defective gene.

A retarded 45-year-old man living in Mexico becomes ill with pneumonia and his family brings him
across the border to the United States. He succumbs to his illness and an autopsy is performed.
Neuropathological examination of his brain reveals neuritic plaques and neurofibrillary tangles.
Which of the following was the most likely cause of this man's retardation?

A. Down's syndrome

B. Edwards' syndrome

C. Fragile X syndrome

D. Patau syndrome

E. Supernumerary Y syndrome

Explanation:

The correct answer is A. Features of Down's syndrome (trisomy 21) in children include mental
retardation, epicanthal folds, dysplastic ears, hypotonia, a horizontal palmar crease (simian
crease), redundant neck skin, and a short trunk. However, most of these children eventually grow
to adulthood. At that point, the aging parents may have to deal with a physically strong and
healthy mentally retarded individual who is experiencing a deterioration in mental function.
This deterioration may be accompanied by aggressive behavior (as in the elderly with Alzheimer's
disease) arising out of the patient's diminishing ability to reason or understand his
environment.

Edwards' syndrome (choice B), or trisomy 18, causes death in infancy. Characteristics include
rocker-bottom feet, low-set ears, micrognathia, congenital heart disease, and mental
retardation.

Fragile X syndrome (choice C) is associated with enlarged testes as well as mental retardation.
The condition is unusual in that it is related to expansion of a CGG repeat sequence located on
the X chromosome.
Patau syndrome (choice D), or trisomy 13, is characterized by severe mental retardation,
microcephaly, microphthalmia, polydactyly, cleft lip and palate, renal defects, and cardiac
abnormalities. Affected infants typically die before the age of 1.

The effects of supernumerary Y chromosomes (choice E; most commonly XYY) include increased
stature, aggressive behavior, and infertility, but a supernumerary Y chromosome is sometimes
found in otherwise normal individuals.

19

A 26-year-old woman and her 29-year-old husband have been trying to have a child for the last 3
years. During this time the woman has had 5 spontaneous abortions. The karyotypes of the mother,
father, and the most recently aborted fetus all contained 46 chromosomes, and all pairs were
normal except for the pairs shown above. The event that led to the child's abnormal karyotype
was

A. adjacent I segregation

B. adjacent II segregation

C. alternate segregation

D. a recombination event within a paracentric inversion

E. a recombination event within a pericentric inversion

Explanation:

The correct answer is B. The couple is experiencing infertility and a high rate of spontaneous
abortions because the father has a reciprocal translocation between chromosome 7 and chromosome
12. His karyotype is 46, XY, t(7;12) (12qter &rarr; 12q23::7p13 &rarr; 7qter; 12pter &rarr;
12q23::7p13 &rarr; 7pter). During meiosis I, the four chromosomes involved in the translocation
will pair together in a structure called a quadrivalent, which is pictured below.

There are three ways that the quadrivalent can separate during meiosis I. They are called
adjacent I, adjacent II, and alternate segregation. Adjacent II segregation occurs only when the
breakpoint of the translocation is so close to the centromere of a chromosome that the cell
cannot distinguish between the centromeres. In this specific case, the fetus received a normal
chromosome 7 and a normal chromosome 12 from his mother. From his father, the fetus received a
normal chromosome 7 and a chromosome composed of 12qter &rarr; 12q23::7p13 &rarr; 7qter. This
gives the fetus a total of three copies of the material from 7p13 &rarr; 7qter, and only one
copy of material from 12pter &rarr; 12q23. Note that the zygote has three copies of the
centromere of chromosome 7, the hallmark of adjacent II segregation. Since the zygote is
unbalanced, it aborts.

Adjacent I segregation (choice A) produces cells that contain different centromeres, but have
duplication and deletions that lead to spontaneous abortion. In this case, the products of
adjacent I segregation would be 12qter &rarr; 12q23::7p13 &rarr; 7qter and the normal chromosome
12, or 12pter &rarr; 12q23::7p13 &rarr; 7pter and the normal chromosome 7.

Alternate segregation (choice C) yields the only outcomes that produce viable progeny. Two
products are produced. One contains a normal chromosome 7 and a normal chromosome 12, and the
second product contains the balanced translocation. This cell has all the information it needs;
it is just arranged in a unique order. In this case, 12qter &rarr; 12q23::7p13 &rarr; 7qter and
12pter &rarr; 12q23::7p13 &rarr; 7pter.
A recombination event within a paracentric inversion (choice D) leads to the formation of an
acentric fragment and a dicentric bridge. This cell will not complete meiosis.

A recombination event within a pericentric inversion (choice E) leads to chromatids that are
duplicated for material on one of the arms and deleted for material on the other arm.

A couple is referred to a specialist for evaluation of their two-and-a-half year old son. The
child has multiple congenital defects including mental retardation, hirsutism, micrognathia, and
cardiac and renal abnormalities. Karyotypes are done of both parents and the child, and the
results are shown above. The event that led to the child's abnormal karyotype was

A. adjacent I segregation

B. adjacent II segregation

C. alternate segregation

D. a recombination event within a paracentric inversion

E. a recombination event within a pericentric inversion

Explanation:

The correct answer is E. An inversion is a chromosomal rearrangement in which the central

segment produced by two breaks is inverted prior to repair of the breaks. Inversions that
include the centromere are called pericentric inversions. Those that do not include the
centromere are called paracentric inversions. Examination of the father's karyotype reveals that
he has a pericentric inversion on one of his chromosome 3s - [inv(3) (p25q21)]. To allow pairing
of homologous material, his homologues will form a loop structure during meiosis I. If a
recombination event occurs with the loop, the chromatids produced by the crossover event will be
duplicated for material on one of the arms and deleted for material on the other arm. An
illustration of these events is given below.

Examination of the third chromosomes of the child reveals that he has one normal chromosome and
a chromosome that is duplicated for q21 qter (ter = terminal) and deleted for p25 pter.

Adjacent I and II segregation (choices A and B) and alternate segregation (choice C) refer to
the possible segregation events undergone by the quadrivalent during anaphase of meiosis I.

The outcome of a crossover event within a paracentric inversion (choice D) is the formation of
an acentric fragment and a dicentric bridge. This cell will not complete meiosis. A reciprocal
translocation event involves the exchange of material between nonhomologous chromosomes. During
meiosis I, the four chromosomes involved in the translocation will pair together in a structure
called a quadrivalent.

During the process of meiosis, a single homologous chromosome pair fails to separate during the
first meiotic division. This failure would be most likely to produce which of the following
conditions if fertilization occurs and an embryo later develops?

A. Balanced translocation

B. Triploidy

C. Trisomy

D. Unbalanced translocation
E. Uniploidy

Explanation:

The correct answer is C. The process described is nondisjunction, which will cause one daughter
cell to have 24 chromosomes while the other will have 22 chromosomes. When a gamete with the
normal 23 chromosomes combines at fertilization with a gamete with 22 or 24 chromosomes, the
embryo will have 47 chromosomes (trisomy) or 45 chromosomes (monosomy). Nondisjunction can
occur
in either the first or second meiotic division.

Balanced translocation (choice A) occurs when non-homologous chromosomes exchange genetic

material in such a way that no critical genetic material is lost.

Triploidy (choice B) is the term used when a cell has 69 chromosomes (3 of each), and can occur
in tumors or when an egg is fertilized by two sperm.

An unbalanced translocation (choice D) occurs when non-homologous chromosomes exchange

genetic
material with a net loss or gain of critical genetic material.

Uniploidy (choice E) is the state of having 23 chromosomes, seen normally in sperm and eggs.

Physical examination of a neonate demonstrates abnormal facies with a small lower jaw, low-set
ears, and a prominent occiput. The feet have a rocker-bottom deformation, and the infant is
hypertonic. Cardiac evaluation demonstrates a ventricular septal defect. Which of the following
is the average life-span for infants with this neonate's syndrome?

A. 2-3 months

B. 1-2 years

C. 4-7 years

D. 15-25 years

E. Normal life expectancy

Explanation:

The correct answer is A. The syndrome described is Edwards' syndrome (trisomy 18), which is
typically characterized by the features noted and additionally causes severe mental retardation,
which would not be recognizable in the neonatal period. This disease is relatively common, with
an incidence of about 1 in 5000 births (Down syndrome has an incidence of 1 in 2000 births). The
average life span is only 2-3 months.

A 6-month-old child with severe mental retardation is brought to a specialty clinic. Physical
examination is remarkable for microcephaly, a cat-like cry, and an anti-mongoloid slant to the
palpebral fissures. This child should be further evaluated for which of the following disorders?

A. Duodenal atresia

B. Hepatocellular carcinoma

C. Nephroblastoma
D. Renal cysts

E. Ventricular septal defect

Explanation:

The correct answer is E. The presentation is classic for cri-du-chat syndrome, caused by a
deletion of the short arm of chromosome 5 (5p-). Approximately one-quarter of such patients have
a ventricular septal defect. Other features of the syndrome include short stature, distorted
laryngeal anatomy, profound mental retardation, microcephaly, a wide nasal bridge, and an anti-
mongoloid slant to the palpebral fissures. The laryngeal malformation causes feeding and
respiratory difficulties, as well as the cat-like cry, which typically disappears by age 1. Many
patients survive to adulthood, but are usually institutionalized.

Transcription of a prokaryotic gene by RNA polymerase yields an mRNA corresponding to a single

polypeptide chain containing 64 amino acids. The mRNA has a 5' untranslated region of 120
nucleotides and a 3' untranslated region of 240 nucleotides. Approximately how many nucleotides
are in the coding region of the mRNA?

A. 64

B. 128

C. 192

D. 424

E. 552

Explanation:

The correct answer is C. Regardless of how long the untranslated regions are, the number of
nucleotides in the coding region of an mRNA is three times the number of amino acids, since
three nucleotides are required to code for each amino acid, and 3 X 64 = 192. In reality, three
nucleotides code for the first amino acid (formyl-methionine in prokaryotes, methionine in
eukaryotes), which may be removed in posttranslational steps, and three nucleotides at the 3'
end (are needed to terminate the process (i.e., a STOP codon), so the actual number would likely
be slightly higher.

A 42-year-old woman is pregnant and undergoes amniocentesis. The results of the amniocentesis
are consistent with trisomy 21, but the woman wishes to carry the pregnancy to term. After
birth, this child will be at increased risk for the development of which of the following
neoplasms?

A. Acute lymphoblastic leukemia

B. Basal cell carcinoma

C. Colon cancer

D. Glioblastoma multiforme

E. Hodgkin's disease

Explanation:
The correct answer is A. In addition to the well-known mental retardation associated with Down's
syndrome (trisomy 21), affected individuals have an increased incidence of a variety of medical
problems. Acute myeloblastic leukemia is seen in newborns and acute lymphoblastic leukemia is
seen in older children. Epilepsy, which can be very difficult to manage, affects up to 10% of
children with Down's. On occasion, the malformed head and neck region can undergo atlantoaxial
dislocation, causing a sudden or progressive quadriparesis. Congenital malformations of the
cardiac system are common (40% of cases), and include (in decreasing order of frequency) atrial
and ventricular septal defects, tetralogy of Fallot, and patent ductus arteriosus. The
development of the hypopharynx is often poor, predisposing to both aspiration pneumonia and
obstruction by enlarged adenoids. Other malformations that occur with lower frequency include
duodenal atresia and imperforate anus. Acquired autoimmune hypothyroidism is frequent. Boys are
infertile; girls are subfertile but can get pregnant. Alzheimer-like changes develop in mid-
adulthood. Visual problems related to strabismus, nystagmus, or myopia are common. None of the
other neoplasms occur with increased frequency in individuals with trisomy 21.

26

In a rural town, 19-year-old boy and his 16-year-old sister have two children by an incestuous
relationship, as shown in the pedigree above. The girl did not have prenatal care for either
child. The second child, a girl, is brought to the emergency room at three months of age because
of seizures. Physical examination is remarkable for hepatomegaly and growth retardation. Serum
chemistries demonstrate severe hypoglycemia and hyperlipidemia. This patient may have a defect
involving which of the following enzymes?

A. Alpha-L-iduronidase

B. Beta-glucocerebrosidase

C. Glucose-6-phosphatase

D. Hexosaminidase A

E. Muscle phosphorylase

Explanation:

The correct answer is C. The presence of hepatomegaly and hypoglycemic seizures suggests that
this is probably a glycogen storage disease. Only two of the enzymes listed are related to
glycogen storage diseases: glucose-6-phosphatase (deficiency produces von Gierke's disease, from
which this patient is suffering) and muscle phosphorylase (choice E; deficiency produces
McArdle's disease). McArdle's disease is relatively mild, causing only muscle weakness beginning
in the second or third decades, so this option can be excluded. Von Gierke's disease is a
glycogen storage disease caused by a deficiency of glucose-6-phosphatase (type Ia), or the
glucose-6-phosphate translocase (type Ib). It typically presents with neonatal hypoglycemia,
hyperlipidemia, lactic acidosis, and ketosis. Failure to thrive is common in early life;
convulsions may occur due to profound hypoglycemia. The glycogen accumulation in von Gierke's
disease occurs primarily in the liver and kidneys, accounting for the enlargement of these
organs. Gout may develop later because of the derangement of glucose metabolism. Von Gierke's
disease, like most enzyme deficiencies, is inherited as an autosomal recessive disorder.

Alpha-L-iduronidase (choice A) is the defective enzyme in Hurler's syndrome, which is associated

with hepatosplenomegaly, dwarfism, skeletal abnormalities, mental retardation, and corneal
clouding.

Beta-glucocerebrosidase deficiency (choice B) causes Gaucher's disease, which is characterized

by hepatosplenomegaly and glucocerebroside accumulation in phagocytic cells.

Hexosaminidase A (choice D) deficiency is associated with Tay-Sachs disease, which is

characterized by progressive neurologic deterioration.

The pedigree above illustrates the mode of inheritance for which of the following diseases?

A. Glucose-6-phosphate dehydrogenase deficiency

B. Leber's hereditary optic neuropathy

C. Neurofibromatosis

D. Sickle cell anemia

E. Tay Sachs disease

Explanation:

The correct answer is A. Glucose-6-phosphate dehydrogenase (G6PD) deficiency (choice A) is an X-

linked recessive disorder that affects the pentose phosphate pathway. The hallmark of X-linked
recessive inheritance is an abundance of affected males and an absence of affected females.
Males are hemizygous for the X chromosome, so the phenotype is expressed with only one dose of
the gene. Females have two copies of the X chromosome, so they appear phenotypically normal
although they may carry the recessive allele. Since a male inherits his X chromosome from his
mother, if he is affected, she must carry the trait. Other X-linked recessives include Lesch-
Nyhan disease, hemophilia A, and Duchenne's muscular dystrophy.

Leber's hereditary optic neuropathy (choice B) is a relatively common cause of acute or subacute
vision loss, especially in young men. It exhibits a mitochondrial inheritance pattern. The
hallmark of this pattern is matrilineal inheritance. All of the children of an affected woman
will be affected since they receive mitochondrial genes only from the female parent. Affected
males do not contribute mitochondria to progeny, so their children will not receive the trait.

Neurofibromatosis (choice C) shows an autosomal dominant inheritance pattern, so the phenotype

will be expressed if the allele is present in one dose. Deleterious autosomal dominants occur at
very low frequencies, so affected individuals are almost always heterozygous for the trait.
Since the gene is located on an autosome, both male and female progeny can be affected. Other
autosomal dominants include Ehlers-Danlos syndrome, Huntington's disease, and osteogenesis
imperfecta.

Sickle cell anemia (choice D) and Tay Sachs disease (choice E) are both inherited as autosomal
recessives. For the phenotype of the autosomal recessive to be expressed, the recessive allele
must be present in two doses. Both male and female children can be affected. The hallmark
feature is that unaffected parents have affected children of both sexes.

A baby is born with a small head, small eyes, and 6 fingers on each hand. Two dimensional
echocardiography reveals congenital heart defects. Which of the following genetic conditions is
most likely to be the cause of this child's presentation?

A. Trisomy 13

B. Trisomy 18

C. Trisomy 21
D. XXY

E. XYY

Explanation:

The correct answer is A. This is Patau syndrome, or trisomy 13. This disorder is also associated
with severe mental retardation, abnormal forebrain structures, and death within one year of
birth. Patau syndrome has an incidence of 1:6000 births, making it the second most common form
of autosomal trisomy.

Trisomy 18 (choice B) is Edwards syndrome, characterized by severe mental retardation, rocker

bottom feet (also sometimes seen in Patau syndrome, so be careful!), low-set ears, micrognathia,
clenched hands, prominent occiput, and death within one year. Edwards syndrome has an incidence
of 1:8000, making it the third most common autosomal trisomy.

Trisomy 21 (choice C) is Down syndrome, and is characterized by mental retardation, flat facial
profile, prominent epicanthal folds, simian crease, duodenal atresia, and congenital heart
disease. Down syndrome is the most common autosomal trisomy, with an incidence of 1:700.

XXY (choice D) is Klinefelter syndrome and is associated with male hypogonadism and infertility,
eunuchoid body habitus, gynecomastia, and lack of male secondary sexual characteristics.

XYY (choice E) is double Y syndrome. Affected individuals often go undetected, but may be taller
than average, and may be more likely to exhibit aggressive, antisocial behavior.

A 43-year-old man is brought to the general medicine clinic by his wife. She states that his
memory has progressively deteriorated over the last several years, and that his personality has
been changing. On examination, the physician notes abnormal, writhing movements of the man's
limbs and hyperreactive patellar reflexes. An MRI of the head reveals a loss of volume in the
neostriatum and cortex. A family history reveals that similar symptoms occurred in several
members of the patient's family. Which of the following genetic mechanisms has been implicated
in this disorder?

A. Expanded trinucleotide tandem repeat

B. Genomic imprinting

C. Large deletion in one gene

D. Single amino acid substitution

E. Translocation

Explanation:

The correct answer is A. The disease described is Huntington's disease, which is now known to be
related to an expanded trinucleotide tandem repeat on the short arm of chromosome 4. The number
of trinucleotide repeats frequently increases in succeeding generations during the process of
spermatogenesis.

Prader-Willi and Angelman syndromes are frequently cited examples of genetic diseases involving
genomic imprinting (choice B).

Duchenne's muscular dystrophy is an example of a disease that is frequently due to a large

deletion in a single gene (choice C).
Single amino acid substitutions (choice D) are common in recessive diseases such as sickle cell
anemia.

Translocations (choice E) occur in disorders such as chronic myelogenous leukemia (CML;

Philadelphia chromosome) and some cases of Down's syndrome.

A 10-year-old boy with the facies and many other critical features of Down's syndrome has an
intelligence quotient (IQ) in the mid-normal range. Which of the following genetic mechanisms
would most likely account for the discrepancy between the child's IQ and his appearance?

A. Balanced translocation

B. Chiasma

C. Mosaicism

D. Spermiogenesis

E. Synapsis

Explanation:

The correct answer is C. Mosaicism is the term used when cells with more than one type of
genetic constitution are present in the same organism. The scenario described in the question
uncommonly occurs when nondisjunction of chromosome 21 occurs during mitosis (rather than
meiosis) in one of the early cell divisions. The degree to which the individual expresses the
characteristics of the syndrome depends on the number of cells involved and their distribution.

Balanced translocation (choice A) does not produce features of any syndrome, because critical
genetic material is not lost, although progeny may be affected when the translocated chromosome
is added to a complement of otherwise normal chromosomes.

Chiasma (choice B) refers to the "X"-shape of chromosomes undergoing exchange of genetic

material in crossover.

Spermiogenesis (choice D) refers to the development of sperm precursors into mature sperm.

Synapsis (choice E) refers to the pairing of homologous chromosomes in the first meiotic
division.

A couple has a daughter who is ataxic and has a seizure disorder. She also has a strange affect
characterized by excessive laughter at inappropriate times. Cytogenetic analysis demonstrates a
normal genotype with 46 chromosomes and no apparent deletions. These symptoms are most likely
due to

A. a point mutation in an autosome

B. confined placental mosaicism

C. expansion of a trinucleotide repeat

D. random inactivation of the X chromosome

E. uniparental disomy
Explanation:

The correct answer is E. The child described is exhibiting the features of Angelman (happy
puppet) syndrome. This disorder is generally caused by a deletion of band q12 in the maternal
copy of chromosome 15, i.e., [(del (15)(q11q13)]. A similar deletion in the paternal chromosome
15 produces Prader-Willi syndrome. The disparate expression of the effects of deletions in the
paternal vs. the maternal chromosomes is called genomic imprinting, and implies that the same
genetic loci are expressed quite differently in maternal and paternal chromosomes. Angelman
syndrome can also occur if uniparental disomy occurs for chromosome 15 such that the embryo
receives two copies of the paternal chromosome 15 without the maternal chromosome 15 to
"balance" the paternal contribution.

Point mutation in autosomes (choice A) has not been associated with Angelman syndrome.

Confined placental mosaicism (choice B) is due to a mutation occurring within trophoblast or

extraembryonic precursor cells of the inner cell mass and is an important cause of intrauterine
growth retardation.

Expansion of a trinucleotide repeat (choice C) is associated with Fragile X syndrome and

Huntington disease.

Random inactivation of the X chromosome (choice D) occurs normally, as postulated in the Lyon
hypothesis.

In the pedigree above, what is the probability that IV.3 is a carrier of this trait?

A. 1/4

B. 1/3

C. 1/2

D. 2/3

E. 1/1

Explanation:

The correct answer is D. Given that both III.1 and III.2 must be carriers since they have
produced affected offspring and the pedigree is obviously that of an autosomal recessive
(multiple affected children from unaffected parents), there is a 2/3 chance that IV.3 is a
carrier. In a cross, there would be a 25% chance that they would be normal, 50% chance that they
would be carriers, and 25% chance that they would be affected. Since we know they are not
affected, we can disregard that probability (25%). This means that we are now dealing with the
remaining 75%, and that the original 50% chance of being a carrier, divided by the remaining 75%
(.50/.75) now equals 66%, or 2/3.

Retinoblastoma is associated with an abnormality in which chromosome?

A. 5

B. 8

C. 13

D. 21
E. X

Explanation:

The correct answer is C. About 20% of patients with chromosome 13 abnormality (13q-syndrome)
develop retinoblastoma. There is also a genetic dominant form of retinoblastoma that has an 80%
penetrance rate. Retinoblastomas that have a genetic basis are more apt to be bilateral than the
spontaneous lesions. Microscopically, retinoblastomas are composed of masses of small
hyperchromatic cells that may form small rosettes composed of radially arranged cells
surrounding a central lumen.

A family is referred to a genetic specialist because of mild mental retardation in several of

the school-age children. Laboratory evaluation demonstrates a specific chromosomal breakage site
in metaphase studies of lymphocytes cultured with methotrexate. Which of the following
chromosomes is most likely to be specifically affected?

A. X

B. Y

C. 13

D. 18

E. 21

Explanation:

The correct answer is A. The heritable mental retardation condition associated with chromosomal
breakage is fragile X syndrome. The break point is at q27.3 on the X chromosome. The test for
this condition involves culturing lymphocytes in either folate-deficient medium or with chemical
agents such as methotrexate that tend to break chromosomes. To make the diagnosis, at least 4%
of metaphase chromosomes must show the specific break-point on the X chromosome. The percentage
of defective X-chromosomes above 4% does not correlate well with the degree of mental
retardation. The breakage point is a site of CGG trinucleotide repeats, which tend to expand in
successive generations, producing the clinical feature of worsening mental retardation in each
generation.

Y chromosome (choice B) damage is not part of fragile X syndrome, but loss of this chromosome is
one mechanism of producing 45, X0 (Turner syndrome), characterized by mental retardation.

Trisomy 13 (choice C, Patau syndrome), trisomy 18 (choice D, Edward's syndrome) and trisomy 21
(choice E, Down's syndrome) are all associated with mental retardation, but not chromosomal
breakage syndromes.

The pregnant mother of a 6-year-old son with glucose&ndash;6-phosphate dehydrogenase deficiency

is very worried that her female fetus will have the disease. The father and mother are
clinically normal. Which of the following is true about her baby?

A. The baby has a 25% chance of clinical disease

B. The baby has a 50% chance of being a carrier

C. The baby has a 50% chance of clinical disease

D. The baby will be a carrier

E. The baby will have clinical disease

Explanation:

The correct answer is B. Glucose-6-phosphate dehydrogenase disease is an X-linked condition. The

father has a normal X chromosome since he does not have clinical disease. The mother has one
normal X chromosome and one defective X chromosome, since her 6-year-old son has the disease and
she does not. Therefore, the female fetus has a 50% chance of having two normal X chromosomes
and a 50% chance of having one normal and one abnormal X chromosome, making her a carrier.

Glucose 6-phosphate dehydrogenase deficiency is a defect in the pentose phosphate pathway of

glucose metabolism, leading to defective production of reduced NADPH. Reduced NADPH is used in
many biochemical pathways, and is specifically used to regenerate the reduced form of
glutathione that protects the body against oxidant drugs.

Examination of a late aborted fetus reveals a small head, small eyes, prominent cleft lip and
palate, 6 fingers on each hand, and dextrocardia. The developmental abnormalities noted in this
fetus were probably due to

A. 5p-

B. 45, XO

C. trisomy 13

D. trisomy 18

E. trisomy 21

Explanation:

The correct answer is C. Chromosomal aberrations are common in spontaneously aborted fetuses.
This fetus has Patau syndrome (trisomy 13). A convenient way to remember trisomy 13 is to think
of polydactyly (remembered as 13 fingers) and midline defects including microphthalmia (rarely
just one central "eye"), cleft lip, palate, or face; arrhinencephalia (failure of development of
olfactory nerves and related brain); and dextrocardia or ventricular septal defect. The head is
usually small, with profound mental retardation. In fetuses that survive until birth, death
usually occurs in the neonatal period. Patau syndrome has an incidence of 1 in 6000 births.

Features of Cri du Chat syndrome (5p-; choice A) include a cat-like cry, severe mental
retardation, microcephaly, and epicanthal folds.

Features of Turner's syndrome (45, X0; choice B) include webbed neck, short stature, broad
chest, low hairline, primary amenorrhea, coarctation of aorta and streak ovaries.

Features of Edwards' syndrome or trisomy 18 (choice D) include severe mental retardation,

ventricular septal defect, micrognathia, rocker-bottom feet, low-set ears, prominent occiput,
and hypotonia.

Features of Down syndrome or trisomy 21 (choice E) include mental retardation, flat nasal
bridge, epicanthal folds, oblique palpebral fissures, dysplastic ears, horizontal palmar crease,
redundant neck skin, short trunk, ventricular septal defect, acute lymphoblastic leukemia, and
neurologic changes similar to those of Alzheimer's disease.
A couple has four children, three girls and a boy. The girls are healthy, but the boy develops
corneal opacities, painful neuropathies, and multiple, violaceous nodules distributed diffusely
over his skin. Two of the daughters marry and have a total of seven children. As shown in the
pedigree above, two of these children develop the same syndrome as did the affected son in the
F1 generation. Which of the following is the likely diagnosis?

A. Fabry's disease

B. Gaucher's disease

C. Krabbe's disease

D. Metachromatic leukodystrophy

E. Niemann-Pick disease

Explanation:

The correct answer is A. Even if you do not remember the features of the individual lipid
storage diseases, it is worth remembering that Fabry's disease (described above) is the only one
in the group with X-linked genetics. As a general rule, you should associate all of the lipid
storage diseases with severe neurologic deterioration. The exception is Gaucher's disease
(choice B), which tends to affect the liver and spares the brain.

Gaucher's disease (choice B), Niemann-Pick disease (choice E), and Type I Tay-Sachs disease are
not X-linked; all occur with greater frequency in Ashkenazi Jews.

You should associate Krabbe's disease (choice C) with the presence of "globoid" cells in
degenerating white matter in the brain.

Metachromatic leukodystrophy (choice D) is caused by a deficiency of the enzyme arylsulfatase A.

A 5-year-old mentally retarded boy is brought to the city from a rural community for evaluation.
A careful history reveals mental retardation in a number of other family members, especially the
males. Physical examination is remarkable for a long face with large ears, a large jaw and
bilateral enlargement of the testes. This presentation is suggestive of

A. Down's syndrome

B. Edward's syndrome

C. Fragile X syndrome

D. Klinefelter's syndrome

E. Turner's syndrome

Explanation:

The correct answer is C. Enlarged testes are the most specific phenotypic feature to suggest
Fragile X syndrome in an individual who appears to have a hereditary mental retardation. The
condition has unusual genetics as it is related to expansion of a CGG repeat sequence located on
the X chromosome. The larger the number of repeats, the higher the probability of significant
retardation, hence the retardation tends to become more severe in successive generations, as
more CGG repeats accumulate. Sisters of affected males tend to show milder retardation than
their brothers.
Features of Down's syndrome (choice A), or trisomy 21, include mental retardation, epicanthal
folds, dysplastic ears, hypotonia, a horizontal palmar crease (simian crease), redundant neck
skin, and a short trunk.

Edwards' syndrome (choice B), or trisomy 18, causes death in infancy. Characteristics include
rocker bottom feet, low set ears, micrognathia, congenital heart disease, and mental
retardation.

Klinefelter's syndrome (47, XXY; choice D) is associated with testicular atrophy, a eunuchoid
body shape, long extremities, and a small penis.

Turner's syndrome (45, X; choice E) produces a female phenotype with short stature, ovarian
dysgenesis and webbing of the neck.

A boy with Duchenne muscular dystrophy (DMD) was born to parents with no family history of the
disease. The most likely explanation for this occurrence is

A. a CGG expansion that resulted in the disruption of the promoter of the dystrophin gene

B. infidelity

C. a point mutation in the dystrophin gene

D. a recombination event in the dystrophin gene that gave rise to a frameshift mutation leading
to an untranslatable mRNA

E. a translocation that resulted in the disruption of the dystrophin gene

Explanation:

The correct answer is D. Duchenne muscular dystrophy (DMD) is a lethal, X-linked recessive
disease affecting approximately 1 in 3300 live male births. The disease becomes symptomatic in
early childhood. Inability to walk occurs by the end of the first decade, and death usually
occurs by the second decade. Nearly all patients show the complete absence of the protein
dystrophin, which is abundant in skeletal and cardiac muscle. The dystrophin gene (or DMD gene),
located at Xp21, is approximately 2300 Kb in size, making it one of the largest known genes of
any species. It contains 24 regions of 109 amino acids that are similar but not identical
repeats of each other. In women, the similarity of these sequences can lead to the misalignment
of homologous material at meiotic synapsis. In association with a recombination event, this
misalignment gives rise to frameshift mutations, leading to an untranslatable mRNA. This series
of events occurs at an extremely high rate of about 1 in 10,000. In fact, one third of DMD cases
in each generation arise from this mechanism.

Diseases such as fragile X syndrome and Huntington disease are caused by the expansion of a
trinucleotide repeat (choice A).

Infidelity (choice B) is not a plausible explanation for the child because the trait is an X-
linked recessive condition. A male child must receive the DMD trait on the maternal X
chromosome. The father of the child contributes only a Y chromosome, and the history stated that
the mother had no family history of the disorder.

DMD in a patient with no family history is not generally due to a point mutation in the
dystrophin gene (choice C).

Rare cases of DMD in females have been caused by an X chromosome-autosome translocation (choice
E) with the breakpoint on the X chromosome within the DMD gene. Because of the translocation,
only the cells in which the normal X chromosome is inactivated survive in the female zygote.
This gives rise to a female who is heterozygous for the DMD gene but phenotypically expresses
the disease.

A 25-year-old man presents with a chief complaint of persistent, high-pitched ringing noises in
his ears. Questioning reveals that he has also been losing his balance lately. CT of the head
demonstrates bilateral tumors involving the vestibulocochlear nerve. Which of the following
chromosomes contains the tumor suppressor gene most likely to be involved in this case?

A. 5q

B. 13q

C. 17q

D. 18q

E. 22q

Explanation:

The correct answer is E. The patient has bilateral acoustic neuromas, probably due to
neurofibromatosis type II (over 90% of patients with NF-2 develop bilateral acoustic neuromas).
This condition is a associated with the NF-2, gene, located on 22q (note all the 2's). Patients
often develop meningiomas, gliomas, and schwannomas of cranial and spinal nerves.

5q (choice A) contains the APC tumor suppressor gene, which is associated with familial and
sporadic colorectal cancers.

13q (choice B) contains the Rb tumor suppressor gene, which is associated with retinoblastoma
and osteosarcoma.

17q (choice C) contains both the NF-1 tumor suppressor gene, which is associated with
neurofibromatosis type I, and the p53 tumor suppressor gene, associated with many human cancers.

18q (choice D) contains both the DCC gene, which is associated with colon and gastric carcinomas
and the DPC gene, associated with pancreatic cancer.

Tay-Sachs disease, an autosomal recessive disease caused by a deficiency of hexosaminidase A, is

lethal in childhood. In a population of Ashkenazi Jews, blood testing shows the frequency of
heterozygotes to be 0.1. What is the probability that the first child of two individuals from
this population with no family history of the disease will have Tay-Sachs?

A. 0.25

B. 0.11

C. 0.0625

D. 0.0025

E. Cannot be calculated from the information given

Explanation:
The correct answer is D. Since Tay-Sachs is lethal in childhood, the only adults carrying the
gene are heterozygotes. The only mating that will produce progeny with the disease is the mating
between two heterozygotes. Using the blood test data, the probability that a random individual
is a heterozygote is 0.1. The probability that two heterozygotes will produce a child with Tay-
Sachs disease is 0.25. So, the overall probability that two individuals in the population will
produce a child with Tay-Sachs is (0.1)(0.1)(0.25), or 0.0025.

Choice A, 0.25, could be obtained if the parents are carriers, so the probability of a Tay-
Sachs child is equal to the probability that two heterozygotes will produce a child with the
disease, or 0.25.

Choice B, 0.11, could be obtained if both of the parents had a sibling with Tay-Sachs. This
would mean that the grandparents must have carried the disease, and that their normal children
had a 0.67 chance of carrying the allele. This gives the probability that the parent's child
would have Tay-Sachs as (0.67)(0.67)(0.25), or 0.11.

Choice C, 0.0625, is also incorrect. It is the product of (0.25)(0.25).

Choice E incorrectly assumes that because q2, the frequency of the disease, cannot be
calculated, and hence the allele frequencies cannot be calculated, that an estimate of the
frequency of heterozygotes cannot be made. The problem can be done, however, because the
heterozygote frequency (0.1) was given in the question stem.

A 2-year-old child presents to the pediatrician with hematuria. Examination reveals hypertension
and an abdominal mass. A tumor is localized to the right kidney and biopsy reveals a stroma
containing smooth and striated muscle, bone, cartilage, and fat, with areas of necrosis. The
gene for this disorder has been localized to which of the following chromosomes?

A. 5

B. 11

C. 13

D. 17

E. 22

Explanation:

The correct answer is B. This is a tough two-step style question. You first needed to make the
diagnosis, and then you needed to recall the localization of this particular disease to a
specific chromosome. In this case, everything in the vignette leads you to a diagnosis of Wilms'
tumor. Wilms' tumor occurs in children and typically presents with an abdominal mass as well as
with hypertension, hematuria, nausea, and intestinal obstruction. Because the tumor is derived
from mesonephric mesoderm, it can include mesodermal derivatives such as bone, cartilage, and
muscle. The Wilms' tumor suppressor gene (WT-1) has been localized to chromosome 11 (11p).

The remaining answer choices provide us the opportunity to discuss some other known
relationships between genes and disease. This is a topic of intense research that is likely to
become more and more emphasized on the USMLE examinations.

Chromosome 5 (choice A) is the site of the tumor suppressor gene APC, which is involved in the
pathogenesis of colon cancer and familial adenomatous polyposis.

Chromosome 13 (choice C) is the site of the tumor suppressor gene for retinoblastoma and
osteosarcoma (Rb) as well as the BRCA-2 gene for breast cancer.

Chromosome 17 (choice D) is the site of p53 (involved in most human cancers), NF-1
(neurofibromatosis type I), and BRCA-1 (breast and ovarian cancer).

Chromosome 22 (choice E) is home to the NF-2 gene, which is involved in neurofibromatosis type
II.