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Chromosomal Genetic Disease: Structural Aberrations

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Chromosomal Genetic
Disease: Structural
Aberrations
Charleen M Moore, University of Texas Health Science Center at San Antonio, San Antonio,
Texas, USA
Robert G Best, University of South Carolina School of Medicine, Columbia, South Carolina, USA
Structural chromosome rearrangements are changes in the physical structure of
chromosomes that may result in birth defects, mental retardation and increased risk for
infertility or pregnancy loss.
Introduction
Structural chromosomal aberrations can result in genetic disease due to
trisomy and/or monosomy of chromosomal segments. These aberrations
may be de novo events or may be inherited from carrier parents. Structural
abnormalities are formed by chromosomal breakage or unequal crossing-
over which result in deletions, ring chromosomes, duplica- tions,
translocations, insertions and inversions. A single break in one
chromosome will produce a terminal deletion, whereas two breaks in a
single chromosome can result in an interstitial deletion, a ring
chromosome or an inversion. Two breaks in two different
chromosomes can produce structural changes including reciprocal and
Robertsonian translocations. Unequal crossing-over can result in dupli-
cations or deletions.
Chromosome rearrangements are considered balanced if disomy is
maintained for all of the autosomes and a normal complement of sex
chromatin is present, even if the positions of the homologous segments
on the chromo- somes have been changed. In contrast, when chromatin is
lost or gained in the process the rearrangement is said to be unbalanced.
Unbalanced constitutional rearrangements are generally associated
with developmental delay or intellectual impairment, birth defects
and poor growth, whereas balanced rearrangements often have no effect
on physical or intellectual development. Structural chromo- some
rearrangements that are present at conception affect every cell and are
referred to as constitutional. Rearrange- ments that occur later in
development affect only a portion of the cells and result in mosaicism.
Structural abnormal- ities that occur after birth are referred to as acquired
and may cause tumours or leukaemia by altering cell cycle
regulation.
A standard nomenclature has been developed to describe each
of the types of abnormality found in human chromosomes. The current
version was developed by the International Standing Committee on
Human Cytogenetic Nomenclature and adopted in 1995 (ISCN,
1995). It is
ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net
Secondary article
. Introduction
Article Contents
. De Novo Versus Inherited Abnormalities
. Deletions
. Duplications: Gene Duplications and Segmental
Duplications
. Translocations
. Inversions
. Conclusions
accepted throughout the world as the definitive work for
describing and designating both constitutive and acquired chromosomal
abnormalities.
Chromosomal abnormalities due to structural aberra- tions make up
a significant portion of chromosomal genetic disease. Jacobs (1977)
summarized data from seven separate newborn series of 48 650 infants in
Europe and North America that were carried out before the develop-
ment of banding techniques. Balanced structural rearran- gements
included Robertsonian translocations, with a frequency of
approximately 1 in 1100, reciprocal translo- cations (about 1 in 1300)
and inversions (1 in 7 000). Unbalanced structural rearrangements were
less common and included Robertsonian and reciprocal translocations (1
in 16 000), inversions and deletions (1 in 8100) and other unbalanced
karyotypes (1 in 3200). At birth, then, structural rearrangements,
both balanced and unbalanced, were found in approximately one of every
400 infants.
De Novo Versus Inherited Abnormalities
Balanced or unbalanced structural abnormalities may be inherited from
a carrier parent or may occur as de novo rearrangements, being formed in
a single gamete or zygote. If a balanced structural rearrangement is inherited,
there is a low risk for physical or mental impairment resulting from the
rearrangement. However, when the abnormality occurs as a de novo
event, i.e. when the parents have normal karyotypes, the risk for
genetic disease or phenotypic effects is increased, even when the
rearrange- ment appears balanced. This may result from either
submicroscopic deletions or duplications at the break- points or from
functional changes in the genes near the breakpoints, which are caused
by breakage within the gene or by changes in gene regulatory regions.
For a balanced carrier (heterozygote), the only pheno- typic
problem may be difficulties in reproduction
1

evidenced by infertility, spontaneous abortion or abnor- mal offspring.
These difficulties arise from abnormal pairing and segregation at the
first meiotic prophase when homologous pairing and recombination
take place.
The consequences of balanced rearrangements that are identified
prenatally are especially difficult to predict, particularly when they
are de novo in origin. To provide guidelines for risks for de novo
rearrangements detected prenatally, Warburton (1991) surveyed major
laboratories in the United States and Canada and reported the results of
amniocenteses in which apparently balanced de novo
rearrangements were found. These results were compiled from over 377
000 pregnancies. The risk for a serious congenital anomaly was 6.1%
when a reciprocal transloca- tion was found, 3.7% for Robertsonian
translocations and 9.4% for inversions. These values must be weighed
against the overall risk for congenital abnormalities of 2–3% in the general
population. Using this comparison, there is little or no increased risk for de
novo Robertsonian translocations, but there is a 2–3-fold increased risk for
de novo reciprocal translocations or inversions.
Deletions
Abnormalities in which a portion of chromatin from a single
chromosome is lost are called deletions. Deletions result in a partial
monosomy and are, therefore, unba- lanced rearrangements. Single
breaks cause terminal deletions with a subsequent loss of the
chromosome end. When two breaks occur in the same arm of a
chromosome, interstitial deletions are formed by a loss of the chromatin
between the breaks and a rejoining of the remaining segments.
Deletions that are large enough to be visible to the eye using light
microscopy represent the loss of many genes that are physically located in
the same band or region of the chromosome, and result in monosomy
for that portion of the genome. For many loci, this represents a haplo-
insufficiency in function and is often severe enough to cause death of the
embryo. Deletions that survive to birth are associated with a very high
risk of birth defects and intellectual impairment. Those that involve
tumour suppressor genes confer a high risk of cancer and/or
leukaemia.
Terminal deletions
There are many terminal deletions in human chromosomes that cause well
described syndromes. These require a single break and capping of the
broken end with a telomere (Figure 1a). One of the earliest described and
best delineated syndromes due to a terminal deletion is the cri-du-chat
syndrome with loss of part of the short arm of chromosome
5. This may be due to a very small deletion involving a break at band
5p15.2 or one that includes virtually the
2 ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net
Chromosomal Genetic Disease: Structural Aberrations
entire short arm. The characteristic cat-like cry at birth gives the
syndrome its name, using the French terminol- ogy. The infant has a
round face with wide-set eyes, but the older child and adult develops an
elongated asymmetrical face. There is severe intellectual
impairment.
Individual case reports of terminal deletions have been reported
for most of the human chromosomes. One of the most common terminal
deletions involves the end of the short arm of chromosome 4, which
results in intellectual impairment or developmental delay, micro-
cephaly, large simply folded ears, clefting of the lip and palate, external
genital abnormalities, and characteristic facial features.
Ring chromosomes
A ring chromosome is formed from two terminal deletions (Figure 1b).
There is a break in both the short arm and the long arm, with fusion of
the ends of the centromeric segment and loss of the two terminal
segments. Ring chromosomes represent a form of terminal deletion
with the added feature of being mitotically unstable due to
mechanical problems during replication. Individuals with ring
chromosomes have many of the features of patients with terminal
deletions as well as growth retardation. Three types of ring
chromosome are relatively common: large rings with minimal loss from
the terminal segments of the short and long arms, very small rings
as extra chromosomes in the karyotype, and rings formed from the
X-chromosome, which are generally found in females with features of
Turner syndrome.
Interstitial deletions
The analysis of high-resolution or prometaphase banding patterns led to
the discovery of many syndromes that are due to small interstitial
deletions. Interstitial deletions require two breaks with loss of the
interstitial deletions. Interstitial deletions require two breaks with loss
of the interstitial segment ( Figure 1c). Like terminal deletions partial
monosomies caused by interstitial deletions can produce severe
abnormalities and death of the embryo. It is, therefore, only embryos
with small deletions that are likely to survive. This makes detection by
conventional cytogenetic techniques difficult, and many small interstitial
deletions probably go undetected.
One interstitial deletion that has been studied extensively is a deletion just
below the centromere in chromosome 15. This deletion is found in two
distinct and clinically very different syndromes, Prader–Willi and
Angelman syn- dromes.
Prader–Willi syndrome (PWS) is characterized by intense
hyperphagia, obesity, poor muscle tone, hypoplas- tic genitalia and
moderate intellectual impairment, while Angelman syndrome (AS) is
associated with ataxia,
 Chromosomal Genetic Disease: Structural Aberrations

Lost Lost
Break Break

Break Lost
Break
Break
Lost

(a) Terminal deletion (b) Ring (c) Interstitial deletion

Break Break

Direct Deletion
duplication

(d) Duplication/deletion (e) Reciprocal translocation

A A A A
A B A
B Break B B B
B C C
C C C G C
F
Lost D D E
Break D D
D E D D E E J
E E E
F F F F F I
F G C
Break G G H
Break G Break G G
H H G
H H H H
I I I I I I F
J J J J E
Lost
J J Break
K K K K K K
L L L L L L

(g) Pericentric inversion (h) Paracentric inversion

(f) Robertsonian translocation

Figure 1 Formation of structural rearrangements.

(a) Terminal deletion: formation of a terminal deletion by a single break with loss of the terminal segment.
(b) Ring: formation of a ring chromosome by a break in each arm, loss of the terminal segments and union of the centric segment.
(c) Interstitial deletion: formation of an interstitial deletion by two breaks in the same arm, loss of the interstitial segment, and reunion of the two
remaining segments.
(d) Duplication/deletion: formation of a direct duplication and a deletion from unequal crossing-over.
(e) Reciprocal translocation: formation of a reciprocal translocation by a break in each chromosome and exchange of the noncentric segments.
(f) Robertsonian translocation: formation of a Robertsonian translocation by a break within the centromere of each chromosome, union of the two long
arms and loss of the two short arms, reducing the chromosome number by one.
(g) Pericentric inversion: formation of a pericentric inversion by a break in each arm, 1808 rotation of the centric segment, and reunion of the terminal
segments with the centric segment.
(h) Paracentric inversion: formation of a paracentric inversion by two breaks in the same arm, 1808 rotation of the interstitial segment, and reunion of the
terminal segments with the interstitial segment.

seizures, severe intellectual impairment, delayed or absent speech,
spontaneous outbursts of laughter and character- istic facial features.
Similar, and often identical, deleted segments have been found in
both syndromes. The investigation into the basis for these two unique
syndromes with virtually identical cytogenetic findings has led to an
enhanced appreciation of the role of genomic imprinting in humans.
Imprinted genes are genes that are inactivated when inherited from one
parent, but active when inherited from the other parent, so that there
is a functional
monosomy for this locus. In the critical region for PWS– AS, there are
two separate and oppositely imprinted genes. SNRPN is a gene that is
imprinted by the mother, and closely linked is the UBE3A gene that is
imprinted by the father. Deletions of the critical region for PWS–AS that
are inherited from the father therefore result in PWS due to the maternal
inactivation of the only copy of SNRPN. Conversely, deletions of
the same region when inherited from the mother result in AS
because of paternal imprinting of the only UBE3A gene.

ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net 3

 Chromosomal Genetic Disease: Structural Aberrations

Microdeletions (contiguous gene syndromes)
A special category of interstitial deletions called micro- deletions are
so named because their small size often escapes detection by
conventional cytogenetic methods. Microdeletions are also referred to
as contiguous gene syndromes because they involve the loss of a
series of closely linked genes. There may be variability in the size of the
deletions in different patients, but there are consider- able similarities in
the physical features of patients related to the overlap of deleted
chromosomal segments and the influence of the genes within these
segments. Contiguous gene syndromes may also be the result of small
duplica- tions (see next section). A list of some common contiguous gene
syndromes due to microdeletions or duplications is given in Table 1.
These deletions may involve only 1–2 Mb of deoxyribonucleic acid
(DNA) or less, in the same chromosomal band, and are rarely
visible at the micro- scopic level. Microdeletions must therefore be
detected using molecular cytogenetic methods such as fluorescence in
situ hybridization.
An example of a common interstitial deletion is the deletion
within band 22q11.2 that is related to conotruncal heart malformations,
hearing loss, calcium metabolism defects, dysmorphic facial features,
and developmental delay or intellectual impairment. Both the
DiGeorge sequence and velocardiofacial syndrome are associated with
microdeletions of this region and are thought to be different
manifestations of the same genetic deficiency. It is important to recognize
that these deletions may be carried in the heterozygous state in an
unaffected or very mildly affected parent as well as in the more
severely affected
offspring, and thus they present a significant risk for recurrence in
future offspring.
Duplications: Gene Duplications and
Segmental Duplications
Duplications are unbalanced rearrangements that result in partial trisomy.
Compared with deletions, duplications tend to be somewhat milder in
effect, but they share many of the same clinical features. Duplications are
believed to result primarily from unequal crossing over ( Figure 1d),
especially in regions of the genome where repeat DNA sequences are
found. (Unequal crossing-over may also cause interstitial deletions
by the same mechanism.) Segmental duplications can be oriented in two
ways: direct or inverted. Direct duplications retain the same order of
gene loci and chromosome bands in relation to the centromere as
the parent chromosome, whereas inverted duplications exhibit a
complete reversal of loci and bands contained in the duplication.
Duplications on one chro- mosome produce partial trisomies when
paired with a normal chromosome in a diploid cell. Partial trisomies can
also be caused by translocations or through recombination in inversion
heterozygotes (see below). These are referred to as duplications despite
the difference in the mechanism of formation.
One example of a common chromosome duplication is an inverted
duplication of a segment of the long arm of chromosome 15, which is
generally observed as an extra

Table 1 Contiguous gene syndromes

Syndrome Duplication or deletion Critical chromosomal region
Saethre–Chotzen Deletion 7p21-p22
Grieg cephalopolysyndactyly Deletion 7p13
Williams Deletion 7q11.2
Langer–Giedion Deletion 8q24.1
DiGeorge 2 Deletion 10p13
WAGRa Deletion 11p13
Beckwith–Wiedemann Duplication 11p15
Prader–Willi/Angelman Deletion 15q11-13
Rubenstein–Taybi Deletion 16p13.3
Miller–Dieker Deletion 17p13.3
Smith–Magenis Deletion 17p11.2
Charcot–Marie–Tooth, type 1A Duplication 17p11.2-p12
Alagille Deletion 20p11.2-p12
DiGeorge 1/velocardiofacial Deletion 22q11.2
Cat-eye Duplication 22q11
Kallmann/contiguous genes Deletion Xp22.3
Duchenne muscular dystrophy/contiguous genes Deletion Xp21
a
WAGR; Wilms tumour, Aniridia, Genitourinary anomalies, mental Retardation

4 ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net

 Chromosomal Genetic Disease: Structural Aberrations
dicentric chromosome. The phenotype of patients with this chromosome
is highly variable and dependent upon the size of the duplicated segment,
the parent of origin, and the presence or absence of the critical region for
PWS–AS. Duplication of the proximal long arm of chromosome 22 as an
extra dicentric chromosome (cat eye syndrome) is also relatively
common and is associated with coloboma of the eye, intellectual
impairment and anal atresia. Duplication of the short arm of chromosome
4 produces a contrasting pattern of malformations compared with
deletion of the same region (described above). In both cases, there is
intellectual impairment, microcephaly, skeletal malforma- tions and poor
muscle tone. However, other features are dramatically opposite in
appearance. For example, the forehead and nasal bones are prominent
with a deletion of the short arm of chromosome 4, but appear flat
and hypoplastic with a duplication of the same region. The chin,
which is small in the deletion syndrome, is protruding in children with
the duplication.
Microduplications
Microduplications have also been reported, although they are more rare
than microdeletions, and represent another type of contiguous gene
syndrome. They require the same molecular cytogenetic methods for
detection. The best known of the microduplication syndromes occurs
on the short arm of chromosome 11 (within band p15.5) and results
in Beckwith–Wiedemann syndrome with high birthweight,
omphalocele and overgrowth of the tongue. Unlike most unbalanced
autosomal chromosome rearran- gements, this syndrome does not
typically involve intellec- tual impairment or developmental delay.
Another common microduplication occurs on chromosome 17p and
involves only the gene for peripheral myelin protein 22. This results in a
nerve conduction disorder called Charcot– Marie–Tooth syndrome.
Translocations
Translocations involve breaks in two different chromo- somes with an
exchange of segments. In humans, there are two major types of
translocation: reciprocal translocations in which there is no visual
loss of chromatin, and Robertsonian translocations in which the
long arms of two acrocentric chromosomes are joined with loss of the
two short arms. Ascertainment of both reciprocal and Robertsonian
translocations is often through multiple miscarriages, unbalanced
progeny or infertility.
Reciprocal translocations
Reciprocal translocations are characterized by an ex- change of
chromatin between different chromosomes. A
ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net
single break occurs in each chromosome, and the noncentric
segments are exchanged without the visible loss of any chromatin
(Figure 1e). However, the two new derivative chromosomes may have
very different morphol- ogy depending on the breakpoints. The
carrier of a reciprocal translocation generally has no phenotypic
effects due to the rearrangement except for possible reproductive
abnormalities including infertility, sponta- neous abortions and
abnormal offspring. Translocations that reposition proto-oncogenes can
result in dysregula- tion of the cell cycle and the development of
tumours or leukaemia.
Pairing of homologues at meiosis is altered in transloca- tion carriers.
Rather than normal pairing as bivalents, the two derivative
chromosomes and their two normal homologues pair to form a
cross-shaped quadrivalent at pachytene with each homologous segment
pairing with its counterpart (Figure 2a). Pairing and segregation take
place after DNA replication, so each chromosome consists of two
chromatids and, thus, at each point, the quadrivalent consists of four
chromatids.
There are four basic segregation patterns from a reciprocal
translocation quadrivalent (Figure 2a). In most cases, two
chromosomes move to one daughter cell and two to the other; in rare
situations, three chromosomes segregate together, leaving one to
move alone. Daniel (1979) and Jalbert et al. (1980) have listed ways to
evaluate a pachytene quadrivalent in order to determine the most likely
modes of segregation and viable outcomes. Examin- ing cytogenic data
bases (e.g. Borgaonkar, 1994; Schinzel, 1994) may help to ascertain
whether similar rearrange- ments have been viable.
Alternate segregation
Both normal chromosomes move to one pole and both translocation
chromosomes move to the opposite pole; thus, in a standard
quadrivalent diagram, the chromo- somes found on the diagonals move
to the same poles. All gametes formed from alternate segregation are
balanced.
Adjacent I segregation
Adjacent nonhomologous centromeres move to the same pole. This
results in an unbalanced chromosomal comple- ment that will result in a
zygote with partial trisomy of one chromosome and partial monosomy
of the other when fertilized by a normal haploid gamete. This
segregation pattern often is compatible with viability.
Adjacent II segregation
Adjacent homologous centromeres move to the same pole; this usually
results in large amounts of unbalanced chromatin, which is usually
incompatible with embryonic survival.
5
 Chromosomal Genetic Disease: Structural Aberrations

Reciprocal translocation
chromosomes. Unless the derivative chromosome is small, the embryo
1234
carrier will not be viable.
Other segregation products result from recombination in the centric
segment, giving four other combinations; see ISCN (1995) for a more
Pachytene
detailed description.

Robertsonian translocations
Robertsonian translocations are unique types of whole- arm
14 2 3 1 3 24 3 4 1 2 134
translocations that result from ‘centric fusion’ of the long arms of two
Fertilization by normal gamete acrocentric chromosomes with loss of the short arms, thus reducing the
number of chromosomes by one (Figure 1f). They are named for W. R.
B. Robertson, who was an insect cytogeneticist and studied numerical
1144 1234 1134 1244 1344 1124 11344 chromosome changes in several orthopteran populations (Robertson,
Alternate segregation Adjacent I Adjacent II 3 : 1 (1 of 4) 1916). The formation of a Robertsonian translocation may actually
zygotes zygotes zygotes zygotes result from breaks in the short arm, in the long arm or within the
(a) centromere of the two chromosomes that form the ‘fusion’ product.
Depending on the position of the breaks and exchange of chromatin
Robertsonian translocation segments, the resulting derivative chromosome may be either
1 2 3 carrier monocentric or dicentric. Robertsonian chromo- somes formed of
two homologous long arms (e.g. a chromosome composed of two
chromosome 14 long arms) may be the result of a U-type exchange
Pachytene between sister chromatids or two homologous chromosomes, or
may actually be an isochromosome with identical arms formed by a
misdivision of the centromere.
Participation in Robertsonian translocations is not equal among
the 10 human acrocentric chromosomes. Unbiased ascertainment
13 2 12 23 1 3
data from amniocenteses or consecutive newborn surveys found that a
13;14 transloca- tion is the most common Robertsonian
Fertilization by normal gamete translocation,
Normal Carrier Trisomic Monosomic followed by a 14;21 translocation (Hook and Cross, 1987;
zygote (normal) zygotes zygotes
zygote Therman et al., 1989). However, many families are ascertained
1133 123 1123 1233 113 133
(b) through children with Down syndrome (tris- omy 21), Patau
syndrome (trisomy 13), Prader–Willi
Figure 2 Segregation patterns from reciprocal and Robertsonian syndrome (see above) or unspecified intellectual impair- ment, and,
translocations. After Hirschhorn (1973). therefore, Robertsonian translocations that involve chromosomes 13,
(a) Reciprocal translocation: a pachytene quadrivalent is shown with the 15 or 21 will show an increase in these series. Other ascertainment
results of alternate, adjacent I, adjacent II and 3 : 1 segregation, and
biases may be due to detection of a Robertsonian translocation carrier
fertilization by a normal gamete. Note that only one of the four possible
combinations is represented for 3 : 1 segregation.
through a history of multiple miscarriages or infertility.
(b) Robertsonian translocation: a pachytene quadrivalent is shown with A carrier of a Robertsonian translocation will not generally
the results of the six possible segregation patterns and fertilization by a show any physical effects until reproduction. Then, as in reciprocal
normal gamete. translocations, pairing at pachytene involves both the normal
homologues and the transloca- tion chromosome. However, in the case
of Robertsonian translocations, there are only three chromosomes
in- volved; thus, a trivalent is formed at pachytene. Segrega- tion from
3:1 segregation the trivalent results in the production of six types of gametes (Figure 2b).
Three of the four chromosomes move to one pole and only one moves to Two of these are normal and the other four will produce trisomies or
the opposite pole. (Note that only one type of four possible segregation monosomies when fertilized by a normal gamete. The conceptus
patterns is shown in Figure 2a). This type of segregation often occurs may be viable, depending on which acrocentric chromosomes are
when one of the derivative chromosomes is relatively small. Upon
fertiliza- tion by a normal gamete, the conceptus will have 47

6 ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net

 Chromosomal Genetic Disease: Structural Aberrations
involved. Trisomy for chromosomes 13 and 21 are compatible
with life, whereas trisomy for the other acrocentrics (i.e. 14, 15 and
22) will virtually all be lost as spontaneous abortions. All the
conceptions with mono- somies will also be lost prenatally.
For female carriers of both reciprocal and Robertsonian
translocations, there is an increased risk for abnormal offspring as well
as an increased risk for miscarriages due to inviable products of
conception. The male translocation carrier has an increased risk for
oligospermia or complete azoospermia and often is ascertained through
investiga- tion for infertility.
Sex chromosome–autosome translocation
A special case exists for the X-chromosome when it is involved in a
translocation with an autosome. Female carriers of balanced
X;autosomal translocations may be fertile or may demonstrate
various degrees of gonadal dysgenesis and premature ovarian failure.
The clinical presentation is dependent on the position of the breakpoint in
the X-chromosome. Two critical regions on the long arm of the X-
chromosome in bands Xq13-q22 and Xq22-q27 (a small space within
band Xq22 is not critical) have been identified. If the break is within
these bands, the carrier may have abnormalities in ovarian function; if the
break is outside this region, the carrier will be fertile.
A female with a balanced X;autosome translocation will show
nonrandom X-chromosome inactivation such that, in all cells, the two
translocation X products will be active and the normal X inactive,
probably through selection of cells that are functionally more normal
during mitosis. Females with unbalanced X;autosomal translocations
may be mildly affected due to inactivation of the unbalanced
translocation, producing a functional autosomal monos- omy.
Y;autosome translocations also vary in phenotype depending on
the breakpoint. Y long-arm translocations may involve an acrocentric
short arm and produce no
physical abnormalities, but if involved with other auto-
somes will result in intellectual impairment and infertility.
Inversions
Inversions are formed by two breaks in the same chromosome
with exchange of the two ends. Inversions are thus essentially
formed in the same manner as translocations except that the breaks
and exchange occur in the same chromosome. Two different types of
inversion are found. One is a pericentric chromosome in which one
break occurs in each arm of the chromosome and, thus, the centromere is
included in the inverted segment (Figure 1g). This changes the banding
patterns and may also change the shape of the chromosome due to
movement of the
ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net
centromere. Alternatively, a paracentric chromosome is formed when
both breaks occur in the same arm and, therefore, the centromere is
not included in the inverted segment (Figure 1h). This alters the
banding patterns, but not the shape of the chromosome. Repositioning of
proto- oncogenes in inverted chromosomes can activate onco- genes
and disrupt normal regulation of the cell cycle causing various
forms of cancer.
Pericentric and paracentric inversions
Both pericentric and paracentric inversions can be carried in the
heterozygous state. Like translocation carriers, there is generally no
phenotypic effect on inversion heterozy- gotes due to the inverted gene
order of one homologue, except as a result of abnormalities in meiosis.
Here, as in other heterozygotes for structural rearrangements, diffi-
culties in pairing and segregation arise at the first meiotic prophase during
pachytene when homologous pairing and recombination take place. In
this instance, the inverted segment forms a loop to maximize pairing of
homologous loci between the inverted and normal homologues
(Figure 3).
The inversion loop structure is formed after the chromosomes
have replicated so that the bivalent is composed of four
chromatids, two normal and two inverted strands. Abnormal gametes
are formed only when an unequal number of recombination (crossing-
over) events occurs within the loop structure. As a result of
C C
B B
D D
C C
A A
B D B D
First meiotic anaphase First meiotic anaphase
A C
B D A
B A
D C
A C C C B
B
D
A D
B
D
C
D B A A
C
CD
B D A B
(a) Pericentric inversion (b) Paracentric inversion
Figure 3 Pairing and crossing-over within an inversion loop formed by (a)
pericentric and (b) paracentric inversion heterozygotes, resulting in
abnormal chromatids with duplications and deficiencies. Note that only
two of the four chromatids participate in a single cross-over event. After Srb
et al. (1965).
7

crossing-over, the recombinant chromatid has both a duplicated
segment and a deleted segment, i.e. duplication of the terminal segment of
the short arm with deletion of the terminal segment of the long arm or vice
versa (Figure 3). Since only two of the four chromatids in a bivalent
participate in a single cross-over, any recombinant event produces only
two recombinant chromatids; but also present are one normal
chromatid and one inverted, but balanced, chromatid. It should be noted
that the terminal segments which are duplicated and deleted from crossing-
over are the parts of the chromosome distal to the breakpoints and
are, therefore, the segments outside the loop. Thus, the larger the segment
between the breakpoints (i.e. the closer the breakpoints are to the
telomeres), the larger the loop, and the more likely that recombination will
occur within it. At the same time, the distal segments that are duplicated and
deleted will be smaller. Consequently, it will be more likely for the
recombinant gamete to result in a conceptus that will be abnormal, but
viable. In contrast, the smaller the segment between breakpoints, the less
likely it is that a cross-over will take place in this region.But the
recombinant products that are formed are less likely to come to term
because of the larger duplicated and deleted
segments and, instead, result in miscarriage.
The major difference between pericentric and para- centric
inversions involves the position of the centromere in the recombinant
products. Since the region within the inversion loop remains balanced,
the recombination products of the pericentric inversion each retain a
single copy of the centromere and can, therefore, disjoin normally
during mitosis. In contrast, because the region outside the inversion
loop is either duplicated or deleted, the recombination products from the
paracentric inversion receive either two copies or no copies of the
centromere, neither of which is compatible with long-term survival. On
rare occasions, recombination products with a single active centromere
have been reported from paracentric inver- sions, which allow the
embryo to survive.
Conclusions
Structural aberrations make a significant contribution to genetic disease.
Structural rearrangements are formed from chromosomal breakage and
rejoining, which affects the content and shape of one or more
chromosomes and alters the distribution of genes within the
genome. Heterozygous carriers have an increased risk for infertility,
miscarriages and chromosomally unbalanced offspring with multiple
congenital abnormalities and intellectual impairment. Partial
monosomies in these offspring gen- erally result in more severely affected
infants than trisomies of the same region. There is also an increased
risk for physical and mental abnormalities in carriers of de novo
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8 ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net
Chromosomal Genetic Disease: Structural Aberrations
balanced reciprocal translocations and inversions. Struc- tural
rearrangements, both balanced and unbalanced, have the potential to alter
the control of cell cycling and may result in tumours and
leukaemias.
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