Introductory article
Article Contents
. Introduction
. Chromosome Abnormalities
. Outline of Chromosome Syndromes
. Maternal Age Effects
Introduction
With the discovery in 1956 that the correct chromosome
number in humans is 46, the new era of clinical cytogenetics
began its rapid growth. During the next few years, several
major chromosomal syndromes with altered numbers of
chromosomes were reported, i.e. Down syndrome (trisomy
21), Turner syndrome (45,X) and Klinefelter syndrome
(47,XXY). Since then it has been well established that
chromosome abnormalities contribute signicantly to
genetic disease resulting in reproductive loss, infertility,
stillbirths, congenital anomalies, abnormal sexual development, mental retardation and pathogenesis of malignancy. Specic chromosome abnormalities have been
associated with over 60 identiable syndromes. They are
present in at least 50% of spontaneous abortions, 6% of
stillbirths, about 5% of couples with two or more
miscarriages and approximately 0.5% of newborns. In
women aged 35 or over, chromosome abnormalities are
detected in about 2% of all pregnancies. Some of the
abnormalities and their clinical consequences will be
discussed in the following sections.
. Recurrence Risks
. Summary
Chromosome Abnormalities
Numerical abnormalities
Chromosome abnormalities are classied as either numerical or structural and may involve more than one
chromosome. In discussing numerical abnormalities,
certain terms need to be claried. The normal human
chromosome complement consists of 46 chromosomes
(diploid) which is double the euploid (haploid) or gamete
complement of 23. Exact multiples of euploid chromosome
sets are either diploid or polyploid, i.e. triploid or
tetraploid consisting of three or four euploid sets,
respectively. Aneuploidy refers to the presence of an extra
copy of a specic chromosome, or trisomy, as seen in
Structural abnormalities
Structural rearrangements frequently alter chromosome
morphology. Chromosome morphology is based upon
location of the centromere or primary constriction that
divides a chromosome into a short arm p and a long arm
q (Figure 3a). Chromosomes are metacentric when the
centromere is in the middle with short and long arms of
roughly equal length (Figure 3i), submetacentric when the
centromere is closer to one end with short and long arms of
unequal length (Figure 3a), and acrocentric when the
centromere is near one end with very small short arms
(Figure 3l). The centromere is essential for correct segregation of chromosomes during cell division. DNA replication
prior to cell division ensures that each chromosome
2
Percentage
Trisomies
45,X
Triploidy
Translocations
52
18
17
24
Figure 3 Chromosome structural rearrangements, described in the text. (a) Chromosome arm and numerical banding designations according to
ISCN (1995). (b) Terminal deletion and (c) interstitial deletion, each with loss of acentric fragment. (d) Pericentric inversion and (e) paracentric
inversion, each with rotation of segment between breaks. (f) Direct duplication and (g) inverted duplication. (h) Isochromosome generation for short and
long arms. (i) Ring chromosome with two acentric fragments. (j) Insertion of segment from one chromosome into a nonhomologous chromosome.
(k) Reciprocal translocation with exchange of segments between nonhomologous chromosomes. (l) Robertsonian translocation between two
acrocentric chromosomes. (Illustration prepared by Dave McDonald.)
Trisomy 21
Trisomy 18
Trisomy 13
XXX
XXY
XYY
3549
19 672
9.1
2.5
0.6
1.0
1.3
0.5
Spontaneous
abortions (%)
24
Prenatal
diagnosis (%)
Newborn (%)
0.4
0.2
0.11
0.05
Unbalanced rearrangements
Unbalanced rearrangements usually result in signicant
clinical abnormalities due to loss, duplication or both (in
some cases) of genetic material. Some examples of
unbalanced rearrangements are deletions, duplications,
rings and isochromosomes (Figure 3).
Deletions result in loss of chromosome material from a
single chromosome. Terminal deletions result from a single
break within one chromosome arm with loss of material
distal to the break (Figure 3b). Interstitial deletions involve
two breaks within the same chromosome arm with loss of
the material between the breaks (Figure 3c). Ring chromosomes are formed by breaks occurring in each chromosome
arm with loss of material distal to the breaks and with
subsequent rejoining of the broken ends (Figure 3i). Ring
chromosomes vary in size depending upon how much
material has been lost. They are often unstable during cell
division and can, very rarely, be transmitted from parent to
ospring.
Duplication of a chromosome segment usually occurs by
unequal crossing over between homologous chromosomes
or sister chromatids (Figure 3f). Duplications can also result
from abnormal meiotic segregation in a translocation
(Figure 3k,l) or meiotic crossing over in an inversion
(Figure 3d,e) carrier. In general, duplications are less
harmful than deletions but they inevitably are associated
with some clinical abnormalities. The degree of clinical
severity is correlated with size of the duplicated segment.
An isochromosome is a chromosome consisting of two
identical copies of one arm and none of the other (Figure 3h).
In a person with 46 chromosomes, an isochromosome
results in partial monosomy and partial trisomy. Isochromosomes most likely result from exchange between
homologues during meiosis, or from breakage and reunion
of sister chromatids near the centromere. Centromere
misdivision during meiosis II is also considered to be a
are produced. Pericentric inversions can produce recombinants with duplication and deciency of chromosome
segments. The viability of these recombinant products is
dependent upon the size of the unbalanced segments.
Recombinant chromosomes derived from paracentric
inversions are typically acentric or dicentric and usually
result in nonviable ospring since these chromosomes are
unstable during cell division.
Translocations result from the exchange of chromosome
segments between two or more nonhomologous chromosomes. There are three types of translocations: reciprocal,
Robertsonian and insertional. Reciprocal translocations
are produced by the exchange of broken-o segments
between two dierent chromosomes (Figure 3k). Carriers of
balanced reciprocal translocations are usually normal but
they have an increased risk for unbalanced ospring. The
actual risk is associated with segregation of the translocation components, position of breakpoints and centromere
location. In general, viability is correlated with size of the
unbalanced segment. Robertsonian translocations involve
two acrocentric chromosomes that join near their centromeres, to form a single chromosome (Figure 3l). Frequently,
this single chromosome has two centromeres, resulting in a
dicentric chromosome. Balanced Robertsonian translocation carriers have only 45 chromosomes including the
dicentric chromosome. Carriers of balanced Robertsonian
translocations are usually clinically normal but have an
increased risk of unbalanced ospring. This risk is higher
for female carriers since males frequently have infertility
problems. An insertional translocation is the result of three
breaks such that a nonreciprocal change occurs when the
segment from one chromosome is inserted into another
chromosome (Figure 3j). Insertions are relatively rare since
they involve three breaks. Insertion carriers are clinically
normal but have an increased risk for ospring with partial
monosomy or partial trisomy for the inserted segment.
Table 5 Clinical features of patients with common autosomal or sex chromosome aneuploidy
Syndrome
Karyotype
Down
Trisomy 21
Edwards
Trisomy 18
Patau
Trisomy 13
Turner
45,X
Klinefelter
47,XXY
Triple X
47,XXX
XXY
47,XYY
Short, broad hands with single palmar crease, decreased muscle tone, mental
retardation, broad head with characteristic features, open mouth with large tongue,
up-slanting eyes
Multiple congenital malformations of many organs, low-set malformed ears, receding
mandible, small eyes, mouth and nose with general eln appearance, severe mental
deciency, congenital heart defects, horseshoe or double kidney, short sternum,
posterior heel prominence
Severe mental deciency, small eyes, cleft lip and/or palate, extra ngers and toes,
cardiac anomalies, midline brain anomalies, genitourinary abnormalities
Female with retarded sexual development, usually sterile, short stature, webbing of skin
in neck region, cardiovascular abnormalities, hearing impairment, normal intelligence
Male, infertile with small testes, may have some breast development, tall, mild mental
deciency, long limbs, at risk for educational problems
Female with normal genitalia and fertility, at risk for educational and emotional
problems, early menopause
Tall male with normal physical/sexual development, normal intelligence, increased
tendency for behavioural and psychological problems
WolfHirschhorn
4p16.3
Cri du chat
5p15.2
LangerGiedion
8q24.11-q24.13
Chromosome
region
Incidence
Williams
7q11.23
1/20 000
WAGR
PraderWilli
11p13
15q11.2
1/10 000
Angelman
15q11.2
1/10 000
MillerDieker
SmithMagenis
17p13.3
17p11.2
1/25 000
Alagille
20p11.23-p12.2
Catch 22
22q11.2
DiGeorge
22q11.2
Velocardiofacial 22q11.2
1/5000
Chromosome
region duplicated
11p15.5
17p11.2-p12
22pter-q11.2
trisomy 13, trisomy 18, XXX and XXY are also associated
with maternal age (Table 10).
Over 50% of chromosomally abnormal spontaneous
abortions are trisomic for various chromosomes and, as a
group, are more frequently associated with maternal age
when compared to polyploid and nontrisomic abortions.
Other chromosomally abnormal spontaneous abortions
with sex chromosome monosomy (45,X), triploidy, tetraploidy and various other structural abnormalities are not
associated with maternal age.
The risk for aneuploidy increases with maternal age
primarily owing to meiotic nondisjunction errors associated with reduced recombination or crossing over prior
to the rst meiotic division. This relationship has been
demonstrated in Down syndrome patients with trisomy 21.
Using DNA polymorphisms, the extra chromosome 21
was identied to be of maternal origin in over 90% of cases
and in approximately 80% of these cases nondisjunction
occurred during the rst meiotic division. A similar
relationship implicating a higher frequency of maternal
nondisjunction errors has also been reported for trisomy
13, 16, 18, XXX and XXY.
In addition to being associated with various aneuploid
syndromes, the maternal age eect has also been observed
in cases involving structural rearrangements associated
with nondisjunction and segregation errors. Data from
some balanced translocation carriers indicate that the risk
for unbalanced ospring due to 3:1 disjunction increases
with maternal age similarly to the risk pattern for trisomy
21. A maternal age eect has also been reported for some de
novo structural rearrangements, particularly those involving bisatellited supernumerary marker chromosomes.
In contrast to maternal age-related risk for aneuploidy,
younger women (less than 30 years of age) have an
increased recurrence risk for another trisomy 21 pregnancy
above what is normally expected for their age. In women
aged 30 or older, the recurrence risk for trisomy 21 is
similar to their age-related risk. The reason for the higher
recurrence risk in younger women is not known. In cases of
familial Robertsonian translocations involving chromosome 21, the risk for an unbalanced Robertsonian
translocation Down syndrome is higher for women less
At birth
1/1250
1/1400
1/1100
1/900
1/625
1/500
1/350
1/275
1/225
1/175
1/140
1/100
1/25
At amniocentesis
(16 weeks)
1/420
1/325
1/250
1/200
1/150
1/120
1/100
1/75
1/20
than 30 years of age than for those over 30. In this situation,
lack of a maternal age eect can be attributed to knowledge
of being a translocation carrier and the impact of this
knowledge upon the decision to have more children.
Recurrence Risks
Recurrence risks for chromosomal abnormalities depend
upon the type of abnormality, i.e. numerical or structural,
its origin (de novo or familial) and the sex of the carrier
patient. The empirical recurrence risk for trisomy 21 for
parents with normal chromosomes is approximately 1%
and increases to 2% if the mother is aged 40 or over. This
indicates that in younger women the recurrence risk is
increased over what is expected for their age, while in
women 35 years or older the risk is age-related. With the
exception of trisomy 21, the recurrence risk for other
specic aneuploidy or polyploid conditions is rare.
Recurrence risk for unbalanced ospring of carriers with
various structural rearrangements has been derived
empirically (Table 11). Relatively specic risk estimates
are known for more common types of Robertsonian
translocations. The recurrence risk for an unbalanced
Robertsonian translocation Down syndrome child is
dependent upon which parent is the 14/21 or 21/22 carrier.
However, if a person is a 21/21 carrier, the recurrence risk is
100% regardless of which parent is the carrier. For carriers
of 13/14 Robertsonian translocation, the risk for an
unbalanced trisomy 13 ospring is 12%.
Carriers of balanced rearrangements are usually clinically normal but have an increased risk for producing
unbalanced ospring. Risk for unbalanced gametes or
segregation products depends upon location of chromosome breakpoints relative to the centromere and crossover
frequency. Since it is dicult theoretically to predict the
rate of unbalanced ospring to be expected for any
particular structural rearrangement, risk estimates are
based upon pooling of pregnancy outcome data from all
translocation or inversion carriers (Table 11).
More precise risk gures are available, however, for
carriers of t(11;22) translocations since this is probably the
most frequent reciprocal translocation found in humans.
This translocation is often familial, with reduced fertility in
males. Unbalanced probands are nearly always born to
carrier females. The recurrence risk for the unbalanced
Trisomy 21
Trisomy 18
Trisomy 13
XXX
XXY
All chromosome
anomalies
35
36
37
38
39
40
41
42
45
3.9
5.0
6.4
8.1
10.4
13.3
16.9
21.6
44.2
0.5
0.7
1.0
1.4
2.0
2.8
3.9
5.5
0.2
0.3
0.4
0.5
0.8
1.1
1.5
2.1
0.6
0.7
0.7
0.8
1.2
1.5
1.8
2.4
18.0
0.5
0.6
0.8
1.1
1.4
1.8
2.4
3.1
7.0
8.7
10.1
12.2
14.8
18.4
23.0
29.0
29.0
62.0
Modified from Harper (1988) Practical Genetic Counselling, 3rd edn. Wright.
10
Type of rearrangement
Percentage
of unbalanced
ospring
Robertsonian translocations
14/21, female
14/21, male
13/14, both sexes
21/22, female
21/22, male
21/21 both sexes
1015
25
12
1015
12
100
612
20
50
Further Reading
Reciprocal translocations
Pooled, both sexes
Ascertained by unbalanced child
Ascertained by unbalanced child with
small unbalanced segment
Other ascertainment
t(11;22)(q23;q11.2)
Recurrence risk unbalanced t(11;22)
Pericentric inversions
Ascertained by unbalanced child
Other ascertainment
25
57
2
510
2
Summary
11
12