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1. The answer is (C).
A 37-year-old woman has about a 1% risk to have a child with a chromo-
some abnormality and should be offered amniocentesis to detect chromosome abnormali-
ties in the fetus. Trisomy 21 and Turner syndrome occur spontaneously so cytogenetic
studies of the parents would not provide any information on future risk. Parents of a nor-
mal child have the population risk for having a child with a chromosome abnormality so
there is no indication for offering the test.
2. The answer is (B).
Many patients with Turner syndrome are mosaics, that is, they have two
or more cell lines with different karyotypes. Although there is a normal, 46,XX cell line
present, the majority of cells have the 45,X Turner syndrome karyotype and thus some phe-
notypic features of Turner syndrome can be expected.
3. The answer is (B).
The most common cause of Prader-Willi syndrome is a microdele-
tion in the area of the long arm of chromosome 15 between bands q11 and q13. This
area of chromosome 15 is genomically imprinted, so the parent of origin for the chro-
mosome determines what syndrome will occur as a result of the deletion. If the dele-
tion is on the chromosome 15 that came from the father, then Prader-Willi syndrome
will result. Angelman syndrome occurs if the microdeletion is on the maternal chromo-
some 15.
4. The answer is (C).
Carriers of a 13;21 Robertsonian translocation are at risk for having a
child with Robertsonian Down syndrome or Robertsonian trisomy 13. All the other
Robertsonian translocation carriers have Robertsonian translocations that are lethal when
trisomy occurs and most of these conceptions are not even recognized pregnancies. There
may be an increased risk of infertility connected with these Robertsonian translocations,
but no increased risk of having abnormal children.
5. The answer is (B).
During meiosis, the inverted chromosome must pair with its homolog
in a way that forms a loop. Crossing-over within the inversion loop can result in duplica-
tions or deletions of parts of the chromosomes. These duplicated and deleted chromo-
somes are thus in the gamete resulting from the meiosis and when this unbalanced
gamete and a normal gamete fuse, the conceptus will have an unbalanced chromosome
complement.
6. The answer is (B).
A family history of unexplained miscarriages and mental retardation
may indicate that a structural chromosome rearrangement is segregating in the family and
the miscarriages and mental retardation are the result of inheriting unbalanced segregants.
Cytogenetic testing is not indicated for the other choices.
7. The answer is (B).
Klinefelter syndrome, which is the result of a 47,XXY chromosome con-
stitution, is characterized, among other things, by tall stature, gynecomastia, and small
testes. This combination of features is not seen in the other choices.
8. The answer is (D).
Because there is one normal chromosome 22 and one deleted chromo-
some 22, there is a 50% chance of passing one or the other on with each pregnancy.
9. The answer is (A).
FISH analysis of the child’s chromosomes showed that the Prader-
Willi/Angelman (PWA) locus on chromosome 15 was not present. Any unbalanced
rearrangement of chromosome 15 that would have been inherited to cause Prader-Willi in
the child would have to come from the father, since it is the paternally inherited deletion of
chromosome 15 that causes most cases of Prader-Willi syndrome. The father could not be
LWBK274-C11_101-122.qxd 06/02/2009 04:07 PM Page 120 Aptara
carrying a deletion of the PWA locus or he would have Prader-Willi syndrome, which would
certainly be identified by you, the physician. Individuals with Prader-Willi and Angelman
syndromes do not reproduce.
10. The answer is (D).
Although certain Robertsonian translocations involving chromosome 21
and other translocations involving chromosome 21 can result in Down syndrome, the most
common cytogenetic finding in Down syndrome is three copies of chromosome 21, or tri-
somy for chromosome 21. Trisomy 21 is caused by nondisjunction of chromosome 21 dur-
ing meiosis. A nondisjunction of chromosome 21 in mitosis is rare and would lead to
mosaicism for trisomy 21.
11. The answer is (A).
In a deletion, a portion of the chromosome is lost, leaving only one copy
of that area on the homologous chromosome. Since there is only one copy left on the nor-
mal homolog, that chromosome is monosomic for the deleted area.
12. The answer is (C).
The abl proto-oncogene on chromosome 9 and the bcr proto-oncogene
on chromosome 22 are fused by the 9;22 translocation. Deletions of these genes are not
associated with CML.
13. The answer is (C).
Because a Robertsonian translocation leads to the fusion of two chromo-
somes, in this case chromosomes 13 and 21, there is one less chromosome in the karyotype
as a result. The chromosome number thus goes from 46 to 45.
14. The answer is (D).
Both parents should be studied because either parent could be a carrier.
If neither parent is a carrier, this would mean that there was little risk of having another
child with a chromosome abnormality. Carriers of Robertsonian translocations can have
normal children, children who are balanced carriers like themselves or children with chro-
mosome abnormalities. In the case of a 13;21 Robertsonian translocation, the risk of hav-
ing an abnormal child would be
5% if the father is a carrier, and 15% if the mother is a
carrier.
15. The answer is (B).
Carriers of some balanced translocations have a significant risk of having a
child with a chromosome abnormality. Because the couple has already had an abnormal
child, this indicates that viable, abnormal outcomes are possible with this particular bal-
anced translocation and the couple has a significantly elevated risk of having it happen
again.
16. The answer is (A).
A 47,XYY karyotype is usually only detected incidentally to some other
indication for study since there is not an abnormal phenotype associated with it. Males
with this karyotype are just as likely to be viable as those with a normal 46,XY karyotype.
A 47,XX or XY,
18 karyotype can result in a liveborn, but the majority of fetuses with this
karyotype spontaneously abort. Triploids (69 chromosomes) are rarely liveborn and even
then do not usually survive beyond a couple of hours. A large percentage of first trimester
spontaneous abortions have a 47,XX or XY,
16 karyotype.
17. The answer is (D).
In meiosis, a 21;21 Robertsonian translocation chromosome will go into
one of the daughter cells during meiosis I and the other daughter cell will not receive any-
thing. Thus, a 21;21 Robertsonian translation carrier can only produce gametes that are
disomic for chromosome 21 or nullisomic for chromosome 21. When an ovum from a car-
rier female is fertilized with a normal sperm, the union of the sperm with its one copy of
chromosome 21 and the ovum with its two copies of chromosome 21 contained in the
21;21 translocation chromosome will result in three copies of chromosome 21 being pres-
ent in the conceptus and Down syndrome will be the result. The fertilization of a nulli-
somic ovum, with no copy of chromosome 21, by a normal sperm with its one copy of
chromosome 21, will result in a conceptus that is monosomic for chromosome 21 and this
is lethal. Thus, there is almost a 100% chance that any child resulting from this union will
have Down syndrome.
Chapter 11
Cytogenetic Disorders
121
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18. The answer is (B).
Because there are no outstanding phenotypic characteristics associated
with XYY, people with this karyotype are usually only diagnosed accidentally. Individuals
with Fragile X syndrome have, among other phenotypic abnormalities, mental retardation.
Turner syndrome is found only in females.
19. The answer is (C).
In nondisjunction at meiosis II one of the two daughter cells resulting
from cell division in meiosis I would proceed to divide normally during meiosis II, result-
ing in two normal daughter cells. The nondisjunction of the paired chromosome 21s in the
other meiosis I daughter cell would during meiosis II would lead to both chromosome 21’s
going to one daughter cell and no chromosome 21s going to the other daughter cell.
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123
A.
Metabolic reactions within various biochemical pathways are controlled by
enzymes
that
increase the reaction rate by a million fold. In general, metabolic genetic disorders are
caused by mutations in genes that encode for enzymes of various biochemical pathways.
B.
Most metabolic genetic disorders are
autosomal recessive disorders
(see Chapter 4-II)
whereby individuals with two mutant alleles (homozygous recessive) demonstrate clinically
apparent, phenotypic errors in metabolism. A heterozygote is generally normal because the
one normal allele produces enough enzymatic activity to maintain normal metabolism.
C.
The parents of a proband are obligate heterozygotes whereby each parent carries one
mutant allele and is asymptomatic.
II. METABOLIC GENETIC DISORDERS INVOLVING
A. Galactosemia (GAL).
1.
GAL is an autosomal recessive genetic disorder caused by various
missense mutations
in
the
GALT gene
on
chromosome 9p13
for
galactose-1-phosphate uridylyltransferase (GALT)
which catalyzes the reaction galactose-1-phosphate
→
glucose-1-phosphate.
2.
The various missense mutations result either in a
normal glutamine
S
S
arginine
substitu-
tion at position 188 (Q188R) prevalent in northern Europe; a
normal serine
S
S
leucine
sub-
stitution at position 135 (S135L) prevalent in Africa; or a
normal lysine
S
S
asparagine
sub-
stitution at position 285 (K285N) prevalent in Germany, Austria, and Croatia.
3.
The
Duarte variant allele
is caused by a missense mutation which results in a normal
asparagine
→
aspartate substitution at position 314 (N314D) which imparts instability to
GALT whereby affected individuals have 5% to 20% GALT activity compared to normal
individuals.
4. Prevalence.
The prevalence of GAL is 1/30,000 births.
5. Clinical features include:
feeding problems in the newborn; failure to thrive, hypo-
glycemia, hepatocellular damage, bleeding diathesis, jaundice, and hyperammonemia;
sepsis with E. coli, shock, and death may occur if the galactosemia is not treated; galac-
tosemia is one of the conditions tested for on newborn screens in most states.
B. Asymptomatic Fructosuria (AF; or Essential Fructosuria).
1.
AF is an autosomal recessive genetic disorder caused by a mutation in the
KHK gene
on
chromosome 2p23.3-p23.2
for
ketohexokinase (or fructokinase)
which catalyzes the reaction
fructose
→
fructose-1-phosphate.
2. Clinical features include:
asymptomatic presence of fructose in the urine.
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C. Hereditary Fructose Intolerance (HFI; Fructosemia).
1.
HFI is an autosomal recessive genetic disorder caused by a mutation in the
ALDOB gene
on
chromosome 9q21.3-q22.2
for
fructose 1-phosphate aldolase B,
which catalyzes the reaction
fructose 1-phosphate
→
dihydroxyacetone phosphate
D-glyceraldehyde.
2.
The most likely mechanism causing the clinical features of HFI is that the PO
4
3
group
gets sequestered on fructose and therefore is not available for ATP synthesis.
3. Prevalence.
The prevalence of HFI is 1/20,000 births.
4. Clinical features include:
failure to thrive, fructosuria, hepatomegaly, jaundice,
aminoaciduria, metabolic acidosis, lactic acidosis, low urine ketones, recurrent hypo-
glycemia and vomiting at the age of weaning when fructose or sucrose (a disaccharide
that is hydrolyzed to glucose and fructose) is added to the diet; infants and adults are
asymptomatic until they ingest fructose or sucrose.
D. Lactose Intolerance (LI; Lactase Nonpersistence; Adult-Type Hypolactasia).
1.
LI is an autosomal recessive genetic disorder associated with short tandem repeat poly-
morphisms (STRPs) in the promoter region that affects transcriptional activity of the
LCT
gene
on
chromosome 2q21
for
lactase-phlorizin hydrolase
which catalyzes the reaction lac-
tose
→
glucose
galactose.
2.
These STRPs in the human population lead to two distinct phenotypes:
lactase persistent
individuals and
lactase nonpersistent
individuals.
3.
All healthy newborn children up to the age of
5 to 7 years of age have high levels of lac-
tase-phlorizin hydrolase activity so that they can digest large quantities of lactose present
in milk.
4.
Northern European adults (particularly Scandinavian) retain high levels of lactase-
phlorizin activity and are known as
lactase persistent
and therefore
lactose tolerant
.
5.
However, a majority of the world’s adults (particularly in Africa and Asia) lose the high lev-
els of lactase-phlorizin activity and are known as
lactase nonpersistent
and therefore
lac-
tose intolerant
.
6. Clinical findings of lactose intolerance include:
diarrhea, crampy abdominal pain localized
to the periumbilical area or lower quadrant, flatulence, nausea, vomiting, audible borbo-
rygmi, stools that are bulky, frothy, and watery, and bloating after milk or lactose con-
sumption.
E. Glycogen Storage Disease Type I (GSDI; von Gierke).
1. GSDIa
is an autosomal recessive genetic disorder caused by
85 different mutations in the
G6PC gene
on
chromosome 17q21
for
glucose-6-phosphatase
,
which catalyzes the reaction
glucose-6-phosphate
→
glucose
phosphate.
2. GSDIb
is an autosomal recessive genetic disorder caused by
78 different mutations in the
SLC37A4 gene
on
chromosome 11q23
for
glucose-6-phosphate translocase,
which transports
glucose-6-phosphate into the lumen of the endoplasmic reticulum.
3.
GSDIa is commonly (32% of cases in the Caucasian population and 93% to 100% of cases
in the Jewish population) caused by a
missense mutation
which results in a
normal arginine
S
S
cysteine
substitution at position 83 (R83C). GSDIb is commonly (15% of cases in the
Caucasian population and 30% of cases in the German population) caused by a
missense
mutation
which results in a
normal glycine
S
S
cysteine
substitution at position 339 (G339C).
4. Prevalence.
The prevalence of GSDI is 1/100,000 births.
5. Clinical features include:
accumulation of glycogen and fat in the liver and kidney result-
ing in hepatomegaly and renomegaly, severe hypoglycemia, lactic acidosis, hyper-
uricemia, hyperlipidemia, hypoglycemic seizures, doll-like faces with fat cheeks, rela-
tively thin extremities, short stature, protuberant abdomen, and neutropenia with
recurrent bacterial infections.
F. Glycogen Storage Disease Type V (GSDV; McArdle Disease).
1.
GSDV is an autosomal recessive genetic disorder caused by
46 different mutations in the
PYGM gene
on
chromosome 11q13
for
muscle glycogen phosphorylase
,
which initiates glycogen
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