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100

Answers and Explanations

1. The answer is (D).

Tissues preserved in formalin and frozen tissues that have not been prop-

erly cryopreserved do not contain live cells, so they cannot be grown in culture. 

2. The answer is (A).

Peripheral blood is easily obtained and gives high quality cytogenetic

preparations. A skin sample involves minor surgery. A bone marrow biopsy is painful and
generally does not yield high quality cytogenetic preparations. Cheek cells are more appro-
priate for DNA studies because it would be difficult to obtain sufficient numbers of them for
tissue culture and they would probably be too contaminated with bacteria to be grown suc-
cessfully. 

3. The answer is (B).

The deletion is on the “p” or short arm of chromosome 5 at band 15.31.

4. The answer is (C).

Meiotic chromosomes are not suitable for routine cytogenetic analysis.

Metaphase chromosomes are suitable for cytogenetic analysis in general, but mitotic
prometaphase chromosomes are more extended and allow for detailed, high-resolution
cytogenetic analysis. 

5. The answer is (A).

The light Giemsa negative G-bands are GC-rich and contain more genes

than the AT-rich G positive G-bands and the equivalent Giemsa negative R-bands. C-bands
are heterochromatic and do not contain coding sequences. 

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c h a p t e r

11

Cytogenetic Disorders

101

I. NUMERICAL CHROMOSOMAL ABNORMALITIES

A. Polyploidy

is the addition of an extra haploid set or sets of chromosomes (i.e., 23) to the nor-

mal diploid set of chromosomes (i.e., 46).

1. Triploidy

is a condition whereby cells contain 

69 chromosomes

.

a.

Triploidy occurs as a result of either a 

failure of meiosis in a germ cell

(e.g., fertilization

of a diploid egg by a haploid sperm) or 

dispermy

(two sperm that fertilize one egg). 

b.

Triploidy results in spontaneous abortion of the conceptus or brief survival of the live-
born infant after birth. 

c. Partial hydatidiform mole.

A hydatidiform mole (complete or partial) represents an

abnormal placenta characterized by marked enlargement of chorionic villi. A complete
mole (no embryo present; see Chapter 1I-V-B) is distinguished from a partial mole
(embryo present) by the amount of chorionic villous involvement. A partial mole occurs
when ovum is fertilized by two sperm. This results in a 

69, XXX or 69XXY karyotype

with

one set of maternal chromosomes and two sets of paternal chromosomes.

2. Tetraploidy i

s a condition whereby cells contain 

92 chromosomes

.

a.

Tetraploidy occurs as a result of 

failure of the first cleavage division

.

b.

Tetraploidy almost always results in spontaneous abortion of the conceptus with sur-
vival to birth being an extremely rare occurrence.

B. Aneuploidy

is the addition of one chromosome (

trisomy

),

or loss of one chromosome (

mono-

somy

).

Aneuploidy occurs as a result of 

nondisjunction during meiosis.

1. Trisomy 13 (Patau syndrome; 47,

13)

a.

Trisomy 13 is a trisomic disorder caused by an extra chromosome 13.

b. Prevalence.

The prevalence of trisomy 13 is 1/20,000 live births. Live births usually die

by 

1 month of age. Most trisomy 13 conceptions spontaneously abort. 

c. Clinical features include:

profound mental retardation, congenital heart defects, cleft

lip and/or palate, omphalocele, scalp defects, and polydactyly. 

2. Trisomy 18 (Edwards syndrome; 47,

18)

a.

Trisomy 18 is a trisomic disorder caused by an extra chromosome 18.

b. Prevalence.

The prevalence of trisomy 18 is 1/5,000 live births. Live births usually die

by 

2 month of age. Most trisomy 18 conceptions spontaneously abort. 

c. Clinical features include:

mental retardation, congenital heart defects, small facies and

prominent occiput, overlapping fingers, cleft lip and/or palate, and rocker-bottom heels.

3. Trisomy 21 (Down syndrome; 47,

21)

a.

Trisomy 21 is a trisomic disorder caused by an extra chromosome 21. Trisomy 21 is
linked to a specific region on chromosome 21 called the 

DSCR (Down syndrome critical

region). 

Trisomy 21 may also be caused by a specific type of translocation, called a

Robertsonian translocation 

that occurs between acrocentric chromosomes.

b. Prevalence.

The prevalence of trisomy 21 is 1/2,000 conceptions for women 

25

years of age, 1/300 conceptions for women 

35 years of age, and 1/100 conceptions

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in women 

40 years of age. Trisomy 21 frequency increases with 

advanced maternal

age.

d. Clinical features include:

moderate mental retardation (the leading cause of mental

retardation), microcephaly, microphthalmia, colobomata, cataracts and glaucoma, flat
nasal bridge, epicanthal folds, protruding tongue, simian crease in hand, increased
nuchal skin folds, appearance of an “X” across the face when the baby cries, and con-
genital heart defects. Alzheimer neurofibrillary tangles and plaques are found in trisomy
21 patients after 30 years of age. A condition mimicking acute megakaryocytic leukemia
(AMKL) frequently occurs in children with trisomy 21 and they are at increased risk for
developing acute lymphoblastic leukemia (ALL).

4. Klinefelter syndrome (47, XXY)

a.

Klinefelter syndrome is a 

trisomic 

sex chromosome disorder caused by an extra X chro-

mosome. The most common karyotype is 47,XXY but other karyotypes (e.g., 48,XXXY)
and 

mosaics

(47,XXY/ 46,XY) have been reported. 

b.

Klinefelter syndrome is 

found only in males 

and is associated with 

advanced paternal age

.

c. Prevalence.

The prevalence of Klinefelter syndrome is 1/1,000 live male births. 

d. Clinical features include:

varicose veins, arterial and venous leg ulcer, scant body and

pubic hair, male hypogonadism, sterility with fibrosus of seminiferous tubules, marked
decrease in testosterone levels, elevated gonadotropin levels, gynecomastia, IQ slightly
less than that of siblings, learning disabilities, antisocial behavior, delayed speech as a
child, tall stature, and eunuchoid habitus. 

5. Turner syndrome (Monosomy X; 45,X)

a.

Monosomy X is a 

monosomic 

sex chromosome disorder caused by a loss of part or all of

the X chromosome. 

66% of monosomy X females retain the maternal X chromosome

and 33% retain the paternal X chromosome. 

50% of monosomy X females are 

mosaics

[e.g., 45,X/46,XX or 45,X/46, 

i(Xq)]. 

b.

Monosomy X is the only monosomic disorder compatible with life and is 

found only in

females.

c.

The 

SHOX gene

(

sho

rt stature homeobox-containing gene on the 

X

chromosome) which

encodes for the 

short stature homeobox protein

is most likely one of the genes that is

deleted in Monosomy X and results in the short stature of these females. 

d. Prevalence.

The prevalence of monosomy X is 

1/2,000 live female births. There are

50,000 to 75,000 monosomy X females in the U.S. population, although true preva-
lence is difficult to calculate because monosomy X females with mild phenotypes
remain undiagnosed. 

3% of all female conceptions results in monosomy X making it

the most common sex chromosome abnormality in female conceptions. However,
most monosomy X female conceptions spontaneously abort.

e. Clinical features include:

short stature, low-set ears, ocular hypertelorism, ptosis, low

posterior hairline, webbed neck due to a remnant of a fetal cystic hygroma, congenital
hypoplasia of lymphatics causing peripheral edema of hands and feet, shield chest,
pinpoint nipples, congenital heart defects, aortic coarctation, female hypogonadism,
ovarian fibrous streaks (i.e., infertility), primary amenorrhea, and absence of second-
ary sex characteristics. 

C. Mixoploidy.

Mixoploidy is a condition where a person has two or more genetically different

cell populations. If the genetically different cell populations arise from a single zygote, the
condition is called 

mosaicism

.

If the genetically different cell populations arise from different

zygotes, the condition is called 

chimerism

.

1. Mosaicism

A person may become a mosaic by 

postzygotic mutations

that can occur at any time dur-

ing postzygotic life. 

These postzygotic mutations are actually quite frequent in humans and produce genet-
ically different cell populations (i.e., most of us are mosaics to a certain extent). However,
these postzygotic mutations are not usually clinically significant. 

If the postzygotic mutation produces a substantial clone of mutated cells, then a clinical
consequence may occur. 

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BRS Genetics

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The formation of a substantial clone of mutated cells can occur in two ways: the muta-
tion results in an abnormal proliferation of cells (e.g., formation of cancer) or the muta-
tion occurs in a progenitor cell during early embryonic life and forms a significant clone
of mutated cells.

A postzygotic mutation may also cause a clinical consequence if the mutation occurs in
the germ-line cells of a parent (called 

germinal or gonadal mosaicism

). For example, if a

postzygotic mutation occurs in male spermatogenic cells, then the man may harbor a
large clone of mutant sperm without any clinical consequence (i.e., the man is normal).
However, if the mutant sperm from the normal male fertilizes a secondary oocyte, the
infant may have a de novo inherited disease. This means that a normal couple without
any history of inherited disease may have a child with a de novo inherited disease if one
of the parents is a gonadal mosaic.

2. Chimerism.

A person may become a chimera by the fusion of two genetically different

zygotes to form a single embryo (i.e., the reverse of twinning) or by the limited coloniza-
tion of one twin by cells from a genetically different (i.e., nonidentical; fraternal) co-twin.

II. STRUCTURAL CHROMOSOMAL ABNORMALITIES

A. Deletions

are a loss of chromatin from a chromosome. There is much variability in the clini-

cal presentations based on what particular genes and the number of genes that are deleted.
Some of the more common deletion abnormalities are indicated below.

Chapter 11

Cytogenetic Disorders

103

Meiosis II

Meiosis II

Meiosis II

Cell division
of meiosis II

23

23

23

23

24

24

22

22

22

24

22

24

Cell division

of meiosis I

Cell division
of meiosis II

Cell division

of meiosis I

Cell division
of meiosis II

Cell division

of meiosis I

+

23

23

46

Sperm

Normal diploid

A

B

D

C

Trisomy

Monosomy

Oocyte Zygote

23

24

47

Sperm

Oocyte Zygote

=

+

=

Sperm

Oocyte Zygote

+

=

23

22

46

Sperm

Oocyte Zygote

+

=

FIGURE 11-1. Meiosis and nondisjunction. (A)

Normal meiotic divisions (I and II) producing gametes with 23 chromo-

somes. (B) Nondisjunction occurring in meiosis I producing gametes with 24 and 22 chromosomes. (C) Nondisjunction
occurring in meiosis II producing gametes with 24 and 22 chromosomes. (D) Although nondisjunction may occur in either
spermatogenesis or oogenesis, there is a higher frequency of nondisjunction in oogenesis. In this schematic, nondisjunc-
tion in oogenesis in depicted. If an abnormal oocyte (24 chromosomes) is fertilized by a normal sperm (23 chromosomes),
a zygote with 47 chromosomes is produced (i.e., trisomy). If an abnormal oocyte (22 chromosomes) is fertilized by a nor-
mal sperm (23 chromosomes), a zygote with 45 chromosomes is produced (i.e., monosomy).

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1. Chromosome 4p deletion (Wolf-Hirschhorn syndrome; WHS)

a.

WHS is caused by a deletion of the 

Wolf-Hirschhorn critical region (WHCR)

on 

chromo-

some 4p16.3

75% of WHS individuals have a de novo deletion, 13% inherited an

unbalanced chromosome rearrangement from a parent, and 12% have a ring chromo-
some 4.

b. Prevalence.

The prevalence of Wolf-Hirschhorn syndrome is 1/50,000 births, with a 2:1

female/male ratio. 

c. Clinical features include:

prominent forehead and broad nasal root (“Greek warrior hel-

met”), short philtrum, down-turned mouth, congenital heart defects, growth retarda-
tion, and severe mental retardation.

2. Chromosome 5p deletion (Cri du chat; cat cry syndrome)

a.

Cri du chat is caused by a deletion of the 

cri du chat critical region (CDCCR)

on 

chromo-

some 5p15.2

and the 

catlike critical region (CLCR)

on 

chromosome 5p15.3.

80% of cri du

chat individuals have a de novo deletion. In 

80% of the cases, the deletions occur on

the paternal chromosome 5. 

b. Prevalence

.

The prevalence of cri du chat syndrome is 1/50,000 births. 

c. Clinical features include:

round facies, a catlike cry, congenital heart defects, micro-

cephaly, and mental retardation.

B. Microdeletions

are a loss of chromatin from a chromosome that cannot be detected easily,

even by high-resolution banding. FISH is the definitive test for detecting microdeletions. 

1. Prader-Willi syndrome (PW)

a.

PW is caused by a microdeletion of the 

Prader-Willi critical region (PWCR)

on 

chromo-

some 15q11.2-13

derived from the 

father.

b.

PW illustrates the phenomenon of 

genomic imprinting

which is the differential expres-

sion of genes depending on the parent of origin. The mechanism of inactivation (or
genomic imprinting) involves 

DNA methylation of cytosine nucleotides

during gameto-

genesis resulting in transcriptional inactivation.

c.

The counterpart of PW is 

Angelman syndrome

.

Other examples that highlight the role of

genomic imprinting include 

complete hydatidiform moles

and 

Beckwith-Wiedemann

syndrome (BWS)

(see Chapter 1IV).

d.

The paternally inherited 

SNRPN allele

,

which encodes for a 

small nuclear ribonucleo-

protein-associated N protein

is most likely one of the genes that is deleted in PW and

results in some of the clinical features of PW.

d. Prevalence.

The prevalence of PW is 1/10,000 to 25,000 births.

e. Clinical features include:

poor feeding and hypotonia at birth, but then followed by

hyperphagia (insatiable appetite), hypogonadism, obesity, short stature, small
hands and feet, behavior problems (rage, violence), and mild-to-moderate mental
retardation.

2. Angelman syndrome (AS; happy puppet syndrome)

a.

AS is caused by a microdeletion of the 

AS/PWS region

on 

chromosome 15q11.2-13

derived

from the 

mother

.

b.

AS is an example of 

genomic imprinting

(see above). The counterpart of AS is 

Prader-Willi

syndrome

.

c.

The maternally inherited 

UBE3A allele

which encodes for 

ubiquitin-protein ligase E3A

is

most likely one of the genes that is deleted in AS and results in many of the clinical fea-
tures of AS. The loss of ubiquitin-protein ligase E3A disrupts the protein degradation
pathway.

d. Prevalence.

The prevalence of AS is 1/12,000 to 20,000 births.

e. Clinical features include:

gait ataxia (stiff, jerky, unsteady, upheld arms), seizures,

happy disposition with inappropriate laughter, severe mental retardation (only 5 to 10
word vocabulary), developmental delays are noted at 

6 months, and age of onset 1

year of age.

3. 22q11.2 Deletion syndrome (DS)

a.

DS is caused by a microdeletion of the 

DiGeorge chromosomal critical region (DGCR) 

on

chromosome 22q11.2.

90% of DS individuals have a de novo deletion.

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