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Chromosomal Genetic Disease: Structural Aberrations
Chapter · April 2001
DOI: 10.1038/npg.els.0001452
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Chromosomal Genetic
Disease: Structural
Aberrations
Secondary article
Article Contents
. Introduction
. De Novo Versus Inherited Abnormalities
. Deletions
Charleen M Moore, University of Texas Health Science Center at San Antonio, San Antonio,
Texas, USA
. Duplications: Gene Duplications and Segmental
Duplications
. Translocations
Robert G Best, University of South Carolina School of Medicine, Columbia, South Carolina, USA
. Inversions
. Conclusions
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 crossingover which result in deletions, ring chromosomes, duplications, 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 duplications 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 chromosomes 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 chromosome rearrangements that are present at conception affect
every cell and are referred to as constitutional. Rearrangements that occur later in development affect only a portion
of the cells and result in mosaicism. Structural abnormalities 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
accepted throughout the world as the definitive work for
describing and designating both constitutive and acquired
chromosomal abnormalities.
Chromosomal abnormalities due to structural aberrations 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 development of banding techniques. Balanced structural rearrangements included Robertsonian translocations, with a
frequency of approximately 1 in 1100, reciprocal translocations (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 rearrangement appears balanced. This may result from either
submicroscopic deletions or duplications at the breakpoints 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 phenotypic problem may be difficulties in reproduction
ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net
1
Chromosomal Genetic Disease: Structural Aberrations
evidenced by infertility, spontaneous abortion or abnormal 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 translocation 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, unbalanced 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
entire short arm. The characteristic cat-like cry at birth
gives the syndrome its name, using the French terminology. 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, microcephaly, 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 syndromes.
Prader–Willi syndrome (PWS) is characterized by
intense hyperphagia, obesity, poor muscle tone, hypoplastic genitalia and moderate intellectual impairment, while
Angelman syndrome (AS) is associated with ataxia,
ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net
Chromosomal Genetic Disease: Structural Aberrations
Lost
Lost
Break
Break
Break
Break
Break
(a) Terminal deletion
Lost
(c) Interstitial deletion
(b) Ring
Break
Direct
duplication
(e) Reciprocal translocation
A
B
C
Lost
Break
Lost
(f) Robertsonian translocation
Break
Deletion
(d) Duplication/deletion
Break
Lost
D
E
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Break
Break
A
B
C
D
E
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(g) Pericentric inversion
C
D
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B
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E
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(h) Paracentric inversion
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 characteristic 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.
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3
Chromosomal Genetic Disease: Structural Aberrations
Microdeletions (contiguous gene syndromes)
A special category of interstitial deletions called microdeletions 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 considerable 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 duplications (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 microscopic 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 chromosome 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
Grieg cephalopolysyndactyly
Williams
Langer–Giedion
DiGeorge 2
WAGRa
Beckwith–Wiedemann
Prader–Willi/Angelman
Rubenstein–Taybi
Miller–Dieker
Smith–Magenis
Charcot–Marie–Tooth, type 1A
Alagille
DiGeorge 1/velocardiofacial
Cat-eye
Kallmann/contiguous genes
Duchenne muscular dystrophy/contiguous genes
Deletion
Deletion
Deletion
Deletion
Deletion
Deletion
Duplication
Deletion
Deletion
Deletion
Deletion
Duplication
Deletion
Deletion
Duplication
Deletion
Deletion
7p21-p22
7p13
7q11.2
8q24.1
10p13
11p13
11p15
15q11-13
16p13.3
17p13.3
17p11.2
17p11.2-p12
20p11.2-p12
22q11.2
22q11
Xp22.3
Xp21
a
4
WAGR; Wilms tumour, Aniridia, Genitourinary anomalies, mental Retardation
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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 malformations 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 rearrangements, this syndrome does not typically involve intellectual 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
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 morphology 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, spontaneous abortions and abnormal offspring. Translocations
that reposition proto-oncogenes can result in dysregulation of the cell cycle and the development of tumours or
leukaemia.
Pairing of homologues at meiosis is altered in translocation 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. Examining cytogenic data bases (e.g. Borgaonkar, 1994; Schinzel,
1994) may help to ascertain whether similar rearrangements 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 chromosomes found on the diagonals move to the same poles. All
gametes formed from alternate segregation are balanced.
Translocations involve breaks in two different chromosomes 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.
Adjacent I segregation
Reciprocal translocations
Adjacent homologous centromeres move to the same pole;
this usually results in large amounts of unbalanced
chromatin, which is usually incompatible with embryonic
survival.
Reciprocal translocations are characterized by an exchange of chromatin between different chromosomes. A
Adjacent nonhomologous centromeres move to the same
pole. This results in an unbalanced chromosomal complement 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
ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net
5
Chromosomal Genetic Disease: Structural Aberrations
Reciprocal translocation
carrier
1234
Pachytene
chromosomes. Unless the derivative chromosome is small,
the embryo will not be viable.
Other segregation products result from recombination
in the centric segment, giving four other combinations; see
ISCN (1995) for a more detailed description.
Robertsonian translocations
1 4
2 3
1 3
2 4
3 4
1 2
1 3 4
Fertilization by normal gamete
1 1 4 4
1 2 3 4
11 3 4
Alternate segregation
zygotes
13 44
1244
Adjacent I
zygotes
1 134 4
1 1 2 4
Adjacent II
zygotes
3 : 1 (1 of 4)
zygotes
(a)
Robertsonian translocation
carrier
1 2 3
Pachytene
1 3
2
1 2
2 3
1
3
11 3
1 3 3
Fertilization by normal gamete
11 3 3
1 2 3
Normal
zygote
Carrier
(normal)
zygote
11 2 3
1 2 3 3
Trisomic
zygotes
Monosomic
zygotes
(b)
Figure 2 Segregation patterns from reciprocal and Robertsonian
translocations. After Hirschhorn (1973).
(a) Reciprocal translocation: a pachytene quadrivalent is shown with the
results of alternate, adjacent I, adjacent II and 3 : 1 segregation, and
fertilization by a normal gamete. Note that only one of the four possible
combinations is represented for 3 : 1 segregation.
(b) Robertsonian translocation: a pachytene quadrivalent is shown with
the results of the six possible segregation patterns and fertilization by a
normal gamete.
3 : 1 segregation
Three of the four chromosomes move to one pole and only
one moves to the opposite pole. (Note that only one type of
four possible segregation patterns is shown in Figure 2a).
This type of segregation often occurs when one of the
derivative chromosomes is relatively small. Upon fertilization by a normal gamete, the conceptus will have 47
6
Robertsonian translocations are unique types of wholearm translocations that result from ‘centric fusion’ of the
long arms of two 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
chromosome changes in several orthopteran populations
(Robertson, 1916). The formation of a Robertsonian
translocation may actually result from breaks in the short
arm, in the long arm or within the centromere of the two
chromosomes that form the ‘fusion’ product. Depending
on the position of the breaks and exchange of chromatin
segments, the resulting derivative chromosome may be
either monocentric or dicentric. Robertsonian chromosomes 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 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 data from amniocenteses or
consecutive newborn surveys found that a 13;14 translocation is the most common Robertsonian translocation,
followed by a 14;21 translocation (Hook and Cross, 1987;
Therman et al., 1989). However, many families are
ascertained through children with Down syndrome (trisomy 21), Patau syndrome (trisomy 13), Prader–Willi
syndrome (see above) or unspecified intellectual impairment, and, therefore, Robertsonian translocations that
involve chromosomes 13, 15 or 21 will show an increase in
these series. Other ascertainment biases may be due to
detection of a Robertsonian translocation carrier through
a history of multiple miscarriages or infertility.
A carrier of a Robertsonian translocation will not
generally show any physical effects until reproduction.
Then, as in reciprocal translocations, pairing at pachytene
involves both the normal homologues and the translocation chromosome. However, in the case of Robertsonian
translocations, there are only three chromosomes involved; thus, a trivalent is formed at pachytene. Segregation from the trivalent results in the production of six types
of gametes (Figure 2b). Two of these are normal and the
other four will produce trisomies or monosomies when
fertilized by a normal gamete. The conceptus may be
viable, depending on which acrocentric chromosomes are
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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 monosomies 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 investigation 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 monosomy.
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 autosomes will result in intellectual impairment and infertility.
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 protooncogenes in inverted chromosomes can activate oncogenes 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 heterozygotes 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, difficulties 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
D
D
C
C
A
B
A
D
First meiotic anaphase
B
C
A
D
C
A
A
C
B
D
C
C
B
D
A
D
B
A
C
B
D
(a) Pericentric inversion
A
C
B
D
A
B
D
Inversions
D
First meiotic anaphase
B
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
B
A
B
C D
(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).
ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net
7
Chromosomal Genetic Disease: Structural Aberrations
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 crossingover 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 paracentric 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 inversions, which allow the embryo to survive.
Conclusions
References
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Further Reading
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 generally 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
8
balanced reciprocal translocations and inversions. Structural rearrangements, both balanced and unbalanced, have
the potential to alter the control of cell cycling and may
result in tumours and leukaemias.
Gardner RJM and Sutherland GR (1996) Chromosome Abnormalities
and Genetic Counseling, 2nd edn. New York: Oxford University Press.
Ledbetter DH and Ballabio A (1995) Molecular cytogenetics of
contiguous gene syndromes: mechanisms and consequences of gene
dosage imbalance. In: Scriver CR, Beaudet AL, Sly WS and Valle D
(eds) The Metabolic and Molecular Bases of Inherited Disease, pp. 811–
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Rooney DE and Czepulkowski BH (1994) Human Cytogenetics.
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Therman E and Susman M (1993) Human Chromosomes. Structure,
Behavior, and Effects, 3rd edn. New York: Springer.
Vogel F and Motulsky AG (1997) Human Genetics. Problems and
Approaches, 3rd edn. Berlin: Springer.
ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net
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