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Chromosomal Syndromes
and Genetic Disease
Frederick W Luthardt, Swedish Hospital Medical Center, Seattle, Washington, USA
Elisabeth Keitges, Dynacare Northwest, Seattle, Washington, USA
Introductory article
Article Contents
. Introduction
. Chromosome Abnormalities
. Outline of Chromosome Syndromes
. Maternal Age Effects
The normal human chromosome complement consists of 46 chromosomes comprising 22
morphologically different pairs of autosomes and one pair of sex chromosomes. Variation
in either chromosome number or structure frequently results in significant mental
and/or clinical abnormalities. Chromosomal syndromes are associated with specific
chromosomal abnormalities.
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 significantly to
genetic disease resulting in reproductive loss, infertility,
stillbirths, congenital anomalies, abnormal sexual development, mental retardation and pathogenesis of malignancy. Specific chromosome abnormalities have been
associated with over 60 identifiable 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
Figure 1 (Down syndrome karyotype with trisomy 21), or to
the absence of a single chromosome, or monosomy, as seen
in Figure 2 (Turner syndrome karyotype with 45,X).
The most common clinically significant chromosome
abnormalities involving aneuploidy are frequently detected in newborns (Table 1). Although autosomal and sex
chromosome trisomies result in clinical abnormalities they
are more viable than monosomies, with the exception of
monosomy X (45,X Turner syndrome). However, fewer
than 5% of 45,X conceptions actually survive to birth.
Aneuploidy is frequently associated with maternal age and
constitutes a significant portion of chromosome abnormalities observed in spontaneous abortions (Table 2) and
detected prenatally in fetuses (Table 3).
Polyploidy resulting from triploidy (69 chromosomes)
or tetraploidy (92 chromosomes) are lethal conditions
most frequently seen in spontaneous abortions and very
Chromosome Abnormalities
Numerical abnormalities
Chromosome abnormalities are classified as either numerical or structural and may involve more than one
chromosome. In discussing numerical abnormalities,
certain terms need to be clarified. 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 specific chromosome, or trisomy, as seen in
Figure 1 47,XX, 1 21 female Down syndrome karyotype demonstrating
trisomy 21. (Karyotype prepared by Dave McDonald.)
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Chromosomal Syndromes and Genetic Disease
Table 1 Incidence of chromosomal abnormalities in newborns
Type of abnormality
Approximate incidence
Sex chromosome abnormalities in males
47,XXY
1/1080 male births
47,XYY
1/1080
Other
1/1350
Total
1/385
Sex chromosome abnormalities in females
45,X
1/9600 female births
47,XXX
1/960
Other
1/2740
Total
1/660
Autosomal numerical abnormalities in infants
Trisomy 21
1/800 live births
Trisomy 18
1/8140
Trisomy 13
1/19 000
Triploidy
1/57 000
Total
1/695
Figure 2 45,X Turner syndrome karyotype demonstrating monosomy X.
(Karyotype prepared by Dave McDonald.)
rarely in newborns with a short survival time. Triploidy is
more common and is related to abnormal events prior to or
during fertilization: most often triploidy results from two
haploid sperm fertilizing a single haploid egg.
Aneuploid and normal diploid cells can occasionally
exist simultaneously in an individual. This condition is
known as mosaicism and involves two or more distinct cell
populations derived from a single zygote or fertilized egg.
Mosaicism can involve either autosomal or sex chromosomes but most frequently involves sex chromosomes.
Mosaicism is seen in approximately 0.2% of fetuses
prenatally, 1% of Down syndrome patients, 10% of
Klinefelter syndrome patients and over 30% of patients
with Turner syndrome. The clinical significance of mosaicism depends upon the proportion and tissue distribution
of the aneuploid cells. Chimaerism, in contrast, is
distinguished from mosaicism in that the different cell
lines are derived from more than one zygote.
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
Structural abnormalities in infants (autosomes and sex
chromosomes)
Balanced rearrangements
Robertsonian
1/1120 live births
Other
1/965
Unbalanced rearrangements
1/1675
Total
1/395
1/160 live births
All chromosome abnormalities
(autosomes and sex chromosomes)
Modified from Thompson et al. (1991) Genetics in Medicine, 5th edn.
WB Saunders.
Table 2 Relative frequencies of different abnormalities in
chromosomally abnormal spontaneous abortions
Abnormality
Percentage
Trisomies
45,X
Triploidy
Translocations
52
18
17
2–4
Modified from Harper (1988) Practical Genetic Counselling, 3rd edn.
Wright.
consists of two identical sister chromatids joined at the
centromere. Chromosomes normally have one centromere.
A dicentric chromosome has two centromeres (Figure 3l)
and an acentric chromosome has none. At metaphase,
when chromosomes are typically examined, sister chromatids appear fused as a result of the staining method
necessary to produce the banding patterns essential for
chromosome identification (Figures 1 and 2). Each band
and subband has an assigned designation that identifies the
chromosome arm, region and specific number as published
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Chromosomal Syndromes and Genetic Disease
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.)
by the 1995 International System for Human Cytogenetic
Nomenclature (Figure 3a). Banding patterns are necessary
to identify specific structural rearrangements within or
between different chromosomes.
Structural rearrangements involve chromosome breakage and reunion within a single chromosome or between
two or more different chromosomes resulting in either
balanced or unbalanced karyotypes. Rearrangements are
balanced if there is no net change in chromosome material
or unbalanced if there is either a gain (partial trisomy) or
loss (partial monosomy) of chromosome material.
The frequency of structural abnormalities varies considerably in different populations. The highest frequency is
in spontaneous abortions and the lowest in newborns
(Table 4). This reduction can, in part, be explained by fetal
losses prior to birth, particularly in those cases with
significant unbalanced rearrangements.
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Chromosomal Syndromes and Genetic Disease
Table 3 Maternal age related frequency of aneuploid fetuses detected prenatally
Aneuploid rate per 1000
Maternal age range (years)
Total number of fetuses
Trisomy 21
Trisomy 18
Trisomy 13
XXX
XXY
XYY
35–49
19 672
9.1
2.5
0.6
1.0
1.3
0.5
Modified from Schreinemachers et al. (1982) Human Genetics 61: 318–324.
Table 4 Frequency of structural chromosome abnormalities in various populations
Structural
rearrangement
Balanced
Unbalanced
Spontaneous
abortions (%)
冧
2–4
Prenatal
diagnosis (%)
Newborn (%)
0.4
0.2
0.11
0.05
Data from various sources.
Unbalanced rearrangements
Unbalanced rearrangements usually result in significant
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
offspring.
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
4
possible, though less likely, mechanism. The most common
isochromosome involves the long arm of the X-chromosome which is frequently seen in individuals with Turner
syndrome. Most X-isochromosomes are actually dicentric.
Inactivation of one centromere makes this abnormal
chromosome more stable during cell division. Autosomal
isochromosomes also occur and most frequently involve
acrocentric chromosomes with loss of their short arms.
Unbalanced isochromosomes are always associated with
clinical abnormalities owing to their inherent genetic
imbalance.
Balanced rearrangements
Carriers of balanced chromosomal rearrangements are
usually clinically normal if no essential chromosome
material is lost and no genes are damaged by the breakage
and reunion process. However, they can produce unbalanced gametes and have an increased risk for chromosomally abnormal offspring. Balanced rearrangements
include inversions, insertions, reciprocal translocations
and Robertsonian translocations (Figure 3).
Inversions are rearrangements within a single chromosome resulting from two breaks with the intervening
segment being rotated 1808 prior to reconstitution.
Inversions are classified as either pericentric, which have
a single break in each arm (Figure 3d) or paracentric, which
have two breaks in one arm (Figure 3e). Pericentric
inversions frequently produce a change in the relative
arm lengths; paracentric inversions do not but can be
identified by changes in the banding pattern of the
chromosome arm affected. Inversion carriers are usually
clinically normal but may have an increased risk for
offspring with partial trisomy and monosomy. This is
because when chromosomes pair during meiosis an
inversion loop is formed when the inverted segment pairs
with its normal homologue and if an odd number of
crossovers occur, unbalanced recombinant chromosomes
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Chromosomal Syndromes and Genetic Disease
are produced. Pericentric inversions can produce recombinants with duplication and deficiency 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 offspring 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-off segments
between two different chromosomes (Figure 3k). Carriers of
balanced reciprocal translocations are usually normal but
they have an increased risk for unbalanced offspring. 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 offspring. 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 offspring with partial
monosomy or partial trisomy for the inserted segment.
Outline of Chromosome Syndromes
Common autosomal trisomies
Trisomy 21 (Down syndrome) is one of the best-recognized
and most common chromosome disorders. It is the single
most common genetic cause for mental retardation. The
incidence of Down syndrome is approximately 1/800
newborns. The risk for having a child with trisomy 21
Down syndrome increases with maternal age. Clinical
features include mental and growth retardation, characteristic facies and other abnormalities described in Table 5.
Approximately 94% of Down syndrome patients have
trisomy 21 (Figure 1) resulting from meiotic nondisjunction,
the failure of homologous chromosomes or sister chromatids to separate during cell division. In about 95% of cases
the extra chromosome 21 is of maternal origin, and of these
cases approximately 80% are due to an error during
meiosis I. About 4% of Down syndrome patients have an
unbalanced Robertsonian translocation involving chromosome 21. Approximately 60% of these translocations
involve the long arm of chromosome 13, 14, or 15 (most
frequently chromosome 14). About half of these translocations are de novo and half are inherited from a balanced
carrier parent (usually the mother). Nearly 40% of
unbalanced Robertsonian translocations involve only
chromosomes 21 and 22. Most of these ( 90%) involve
21/21 long-arm fusions or isochromosomes and nearly all
are de novo. The rare parent who is a balanced 21/21
isochromosome carrier has a 100% risk for having a viable
offspring with Down syndrome. Female carriers of
balanced 14/21 or 21/22 Robertsonian translocations have
a 10–15% risk for an unbalanced Down syndrome child.
Male carriers have a risk of less than 5%. Mosaicism
involving a mixture of normal diploid cells and trisomy 21
cells is present in about 2% of Down syndrome patients.
Trisomy 18 (Edwards syndrome) is the second most
common autosomal trisomy syndrome. It has a frequency
of about 1 in 8000 live births. Clinical features include
failure to thrive, cardiac and kidney problems and other
congenital abnormalities (Table 5). Postnatal survival is
poor and more than 90% die within the first 6 months.
About 80% are female. The incidence of trisomy 18
increases with maternal age. Very few cases of trisomy 18
mosaicism have been reported. Many features characteristic of trisomy 18 have also been reported in patients with
unbalanced translocations involving all or most of
chromosome 18 long arm. Based upon limited data, the
recurrence risk for trisomy 18 is approximately 1%.
Trisomy 13 (Patau syndrome) is the least common of the
major autosomal trisomies with an estimated incidence of 1
in 20 000 live births. Owing to severe clinical abnormalities
including central nervous system malformations, heart
defects, growth retardation and numerous other congenital anomalies (Table 5), trisomy 13 patients rarely survive
the newborn period. Trisomy 13 is associated with
advanced maternal age. The extra 13 usually results from
a maternal meiotic nondisjunctional error. About 20% of
cases have an unbalanced Robertsonian translocation
involving chromosome 13. Balanced 13/14 Robertsonian
translocation carriers have less than 2% risk of having an
unbalanced trisomy 13 offspring. Trisomy 13 mosaicism is
rare and may be associated with less severe clinical
anomalies.
Common sex chromosome abnormalities
Sex chromosome abnormalities have less severe clinical
anomalies than those associated with comparable autosomal imbalances. This difference can be attributed to
genetic inactivation of all but one X-chromosome in those
cases where multiple copies are present, and the relatively
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Chromosomal Syndromes and Genetic Disease
Table 5 Clinical features of patients with common autosomal or sex chromosome aneuploidy
Syndrome
Karyotype
Main clinical features
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 elfin appearance, severe mental
deficiency, congenital heart defects, horseshoe or double kidney, short sternum,
posterior heel prominence
Severe mental deficiency, small eyes, cleft lip and/or palate, extra fingers 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
deficiency, 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
Data from various sources.
low gene content of the Y-chromosome. Sex chromosome
aneuploidy is relatively common, with overall frequency of
about 1 in 500 live births (Table 1). Some (XXX, XXY,
XYY) are relatively frequent in newborns but rare in
spontaneous abortions. Monosomy X (Turner syndrome),
in contrast, is one of the most common chromosome
abnormalities seen in spontaneous abortions but relatively
rare in newborns.
Turner syndrome (45,X)
The frequency of Turner syndrome is about 1 in 8000
newborn females. Clinical features in newborns often
include webbed neck, low hairline, puffy hands and feet,
wide spaced nipples and cardiovascular problems. Later in
life, these girls are typically short, sexually immature and
infertile (Table 5). Slightly more than 50% of Turner
syndrome patients have a 45,X karyotype (Figure 2). The
remaining Turner patients have other sex chromosome
abnormalities of the X-chromosome involving isochromosomes, short-arm deletions and rings. About 30% of
Turner patients are mosaics consisting of 45,X cells plus
other cells with two or more normal X-chromosomes,
structurally abnormal X-chromosomes or a Y-chromosome.
Approximately 95–99% of 45,X conceptions fail to
survive to term and account for about 18% of chromosomally abnormal spontaneous abortions. The incidence of
45,X is not associated with maternal age. The paternal Xchromosome is missing in about 75% of 45,X patients.
6
Klinefelter syndrome (47,XXY)
Klinefelter syndrome has a frequency of about 1 in 1000
newborn males (Table 1). Unlike Turner syndrome, males
with Klinefelter syndrome are not usually detected in the
newborn period. These individuals are generally normal in
appearance before puberty. After puberty they are
frequently ascertained in infertility clinics or identified by
their small testes, breast enlargement and tall stature
(Table 5). Significant mental retardation is not part of this
syndrome but patients have a higher incidence of educational and emotional problems. Most Klinefelter patients
have a 47,XXY karyotype. At least 10% have mosaicism
involving normal 46,XY cells plus another population of
cells with two or more X chromosomes. Mosaic patients
have more variable clinical features and occasionally may
have relatively normal testicular development.
Cytogenetic and molecular data have indicated that
47,XXY is equally likely to result from a maternal or
paternal meiotic nondisjunctional error. Maternally derived cases are associated with maternal age. Variants of
Klinefelter syndrome include those patients with more
than two X-chromosomes, multiple X-chromosome mosaicism and multiple Y-chromosomes. The presence of
additional X-chromosomes (more than two) is associated
with increasing severity of clinical abnormalities including
mental retardation, sexual development and skeletal
anomalies.
47,XYY syndrome
Approximately 1 in 1000 newborn males have a 47,XYY
karyotype (Table 1). XYY males have no discernible clinical
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Chromosomal Syndromes and Genetic Disease
features at birth or in infancy. Their mental and physical
development is normal and they are fertile (Table 5).
Although most 47,XYY patients are clinically normal,
they tend to be taller than normal and have an increased
tendency for behavioural and learning problems as
children and young adults. Y-chromosome aneuploidy
results from paternal meiotic nondisjunction and is not
associated with maternal age.
Trisomy X syndrome (47,XXX)
The frequency of 47,XXX in newborn females is about 1 in
1000 (Table 1) and is associated with maternal age. Most
XXX females are clinically normal with normal gonadal
function and fertility. However, there is an increased risk
for learning disabilities, reduction in performance IQ,
menstrual problems and early menopause (Table 5). Females with more than three X-chromosomes (XXXX and
XXXXX) have been reported but, in comparison to
47,XXX, are quite rare. These tetra-X and penta-X females
are all mentally retarded and have more severe clinical
problems.
Autosomal deletion and duplication
syndromes
Identification of common autosomal deletions requires
precise chromosomal localization of the missing segment.
Chromosome banding patterns make this localization
possible if the deletion is cytogenetically visible. Detection
of common deletions and also very small deletions not
visible by routine cytogenetic analysis (microdeletions) has
been made possible by fluorescence in situ hybridization
(FISH) technology. This technique involves hybridizing
specific fluorescently tagged DNA probes to metaphase
chromosomes, which are detectable by UV excitation.
Absence of a locus-specific fluorescent probe from one
homologue is indicative of a microdeletion.
Several common autosomal deletion syndromes are
described in Table 6. The critical region for Wolf–Hirschhorn syndrome has been assigned to 4p16.3. In 90% of
cases the deletion is de novo and in 10% it is inherited as an
unbalanced translocation. The deletion is usually visible
cytogenetically, but occasionally it is too small and can
only be identified molecularly with specific DNA probes
utilizing FISH methods. Cri du chat syndrome is one of the
earliest deletion syndromes to be described. It has an
incidence of about 1 in 50 000 births. The critical region has
been mapped to 5p15.2. About 90% of deletions are de
novo and 10% are derived from an unbalanced familial
translocation. Langer–Giedion syndrome is a rare condition with microcephaly and mental retardation. The
critical region has been assigned to 8q24.11-q24.13. A
cytogenetically visible deletion is seen in about 50% of
cases.
More recently, a group of autosomal microdeletions or
contiguous gene syndromes have been identified that have
a consistent but complex phenotype associated with a very
small (usually 5 5 Mb) chromosomal deletion. Although
some microdeletions are cytogenetically visible, the current
method is to identify these syndromes by FISH utilizing
fluorescently labelled DNA probes specific for the deleted
segments. Some of the more common microdeletion
syndromes are described in Table 7. In Williams syndrome
about 96% of patients have a deletion for the elastin gene,
which produces a protein necessary for elasticity of large
blood vessels, skin and other organs. The de novo deletion
is of maternal origin in 61% of cases and paternal in 39%.
Genomic imprinting, the differential expression of alleles
depending on the parent of origin, has been reported for
the maternal deletion group of Williams patients since they
had significantly more severe growth retardation and
microcephaly than the paternal deletion group. Some
genes mapped to the WAGR critical region have also
revealed genomic imprinting. The incidence for Prader–
Willi syndrome and Angelman syndrome is approximately
1 in 10 000 births, respectively. About 60% of Prader–Willi
and Angelman syndrome patients have a cytogenetically
visible deletion in the same region of chromosome 15.
FISH analysis identifies a microdeletion in about 70% of
cases of both syndromes. DNA polymorphism demonstrated that in Prader–Willi syndrome the deleted 15 was of
paternal origin and was of maternal origin in Angelman
syndrome patients. These observations suggested that the
difference in clinical features for patients with identical
Table 6 Common autosomal deletions
Syndrome
Chromosome region deleted
Main clinical features
Wolf–Hirschhorn
4p16.3
Cri du chat
5p15.2
Langer–Giedion
8q24.11-q24.13
Severe growth retardation, midline facial defects, mental retardation,
small head, prominent frontal bone between eyebrows, cleft lip/
palate, cardiac defects, wide-spaced eyes, broad nasal bridge
High-pitched cry, wide-spaced eyes, small chin, small head, round face,
severe psychomotor and mental retardation
Small head, mental retardation, sparse hair, bulbous nose, short
stature, multiple cartilaginous growths on bone surfaces
Data from various sources.
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Chromosomal Syndromes and Genetic Disease
deletions implies differential expression depending upon
parental origin (genomic imprinting). About 30% of
Prader–Willi patients have two copies of maternal
chromosome 15 and no paternal copy, a condition called
uniparental disomy (UPD). Fewer than 5% of Angelman
patients have paternal UPD for chromosome 15. A small
proportion (1% Prader–Willi and 4% Angelman) have
neither deletions nor UPD but have abnormal methylation
patterns (differential expression of imprinted genes) at loci
in 15q11-q13 due to imprinting mutations. At least 20% of
nondeletion, non-UPD 15, normally methylated and
cytogenetically normal Angelman patients have other
genetic mutations. A visible cytogenetic deletion is seen
in about 50% of Miller–Dieker syndrome patients. FISH
analysis identifies a microdeletion in 90% of all Miller–
Dieker patients. Hemizygosity for an interstitial deletion of
chromosome 22q11.2 is associated with variable but
overlapping syndromes known as Catch 22, DiGeorge
syndrome and velocardiofacial syndrome. As a group,
these syndromes have an incidence of about 1 in 5000 births
and may account for 5% of all congenital heart defects.
Cytogenetic deletions are seen in about 30% of these
patients. FISH analysis is much more sensitive and
identifies 85–90% of patients with microdeletions.
Autosomal duplication syndromes are much less common than autosomal deletion syndromes. Several autosomal duplication syndromes are described in Table 8.
Beckwith–Wiedeman syndrome has an incidence of 1 in
13 700 births. Approximately 85% are de novo and 20–
28% of these cases are due to paternal UPD for region
11p15.5. Fifteen per cent of cases are familial, due to
maternal carriers with translocations or inversions with a
breakpoint on 11p. These female carriers are clinically
normal but their offspring may have clinical effects
suggesting a role for genomic imprinting. Cytogenetic
abnormalities are present in 2–3% of Beckwith–Wiedeman patients. The most frequent abnormality is duplication of 11p13!p15 resulting from the unbalanced
segregation of a paternal translocation or inversion. De
novo 11p15.5 duplications of paternal origin have also been
reported in some patients with Beckwith–Wiedeman
syndrome. Patients with duplication or trisomy for
11p15.5 have a higher incidence of clinical abnormalities
than those with normal chromosomes. Charcot–Marie–
Tooth disease type 1A (CMT1A) is the most common
inherited peripheral neuropathy in humans and has a
prevalence rate of 1 in 2500. In most cases CMT1A patients
have normal chromosomes with duplication of DNA
markers within 17p11.2!p12. A number of CMT1A
patients have been reported with cytogenetically visible
duplication of 17p11.2p12, demonstrating that this syndrome is correlated with a gene dosage effect for this
chromosome region. Misalignment of homologous chromosomes resulting in unequal crossing over between nonsister chromatids during meiosis is the most likely
mechanism for this type of de novo chromosome duplication. Cat-eye syndrome results from duplication of the
proximal portion of the chromosome 22 long arm. The
most common form of this duplication is a supernumerary
(extra) dicentric bisatellited chromosome 22 designated as
Table 7 Autosomal microdeletion syndromes
Syndrome
Chromosome
region
Incidence
Main clinical features
Williams
7q11.23
1/20 000
WAGR
Prader–Willi
11p13
15q11.2
1/10 000
Angelman
15q11.2
1/10 000
Miller–Dieker
Smith–Magenis
17p13.3
17p11.2
1/25 000
Alagille
20p11.23-p12.2
Catch 22
22q11.2
DiGeorge
22q11.2
Cardiac anomalies, mental retardation, characteristic facies, growth
retardation, gregarious disposition, connective-tissue problems
Kidney tumour, absence of iris, genital abnormalities, growth retardation
Developmental delay, mental retardation, decreased muscle tone, obesity,
small genitals, excessive appetite, hypopigmentation
Developmental delay, mental retardation, unstable gait, absence of speech,
hyperactivity, spontaneous laughter, hypopigmentation
Smooth brain, small head, small chin, growth failure, cardiac abnormalities
Flat midface, wide head, broad nasal bridge, short fingers and toes, mental
retardation, hyperactivity, short stature, characteristic behavioural
problems
Chronic bile flow suppression, dysmorphic facies, ring-like corneal opacity,
vertebral arch defects, narrowing of heart opening
Cardiac defects, abnormal facies, underdeveloped thymus, cleft palate,
decreased calcium in blood
Underdeveloped thymus and parathyroid glands, facial abnormalities,
cardiac defects
Cleft palate, abnormal nose, developmental delay, cardiac abnormalities
Velocardiofacial 22q11.2
1/5000
Data from various sources.
8
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Chromosomal Syndromes and Genetic Disease
Table 8 Autosomal duplication syndromes
Syndrome
Beckwith–Wiedemann
Charcot–Marie–Tooth
disease type 1A
Cat-eye
Chromosome
region duplicated
11p15.5
17p11.2-p12
22pter-q11.2
Main clinical features
Large tongue, tissue and organ overgrowth, mild mental retardation
Decreased reflexes, progressive distal muscular wasting, decreased
muscle tone, sensory neuropathy
Eye defects, absence of anal opening, skin tags in front of ears,
characteristic facies, renal, skeletal and genital anomalies, mental
retardation
Data from various sources.
inv dup(22)(q11.2). This inverted duplication process
requires breakage at 22q11.2 in each of two sister or nonsister chromatids and produces a chromosome containing
two copies of the cat-eye syndrome critical region
(CESCR) or a total of four copies for the patient. These
patients typically have 47 chromosomes owing to the
presence of the supernumerary inv dup(22)(q11.2).
Chromosome instability syndromes
There are several rare inherited syndromes characterized
by increased rates of spontaneous or induced chromosomal breakage and predisposition to leukaemia and solid
cancers. The most extensively studied of these syndromes,
each caused by a different autosomal recessive gene, are
Bloom syndrome, Fanconi anaemia, ataxia telangiectasia
and xeroderma pigmentosum. These syndromes have
distinctive chromosome aberrations. Bloom syndrome is
characterized by quadriradial formations, which is the
exchange of chromatid segments between two chromosomes, and a high rate of sister chromatid exchange (SCE)
or exchanges between homologous chromosome segments.
Fanconi anaemia patients exhibit a high frequency of
chromosome breakage and nonhomologous chromosome
interchange following exposure to alkylating agents or
ultraviolet radiation. Their SCE rate is normal. Individuals
with ataxia telangiectasia show an increased level of
chromosome breaks and rearrangements and may have
abnormalities involving chromosome 14. These patients
have a normal SCE level. Patients with xeroderma
pigmentosum do not exhibit spontaneous chromosome
breakage; however, rearrangement, breaks, and increased
SCE rate are observed after exposure to ultraviolet
radiation.
Maternal Age Effects
Prenatal and live birth risks for trisomy 21 Down
syndrome are well established and are clearly associated
with maternal age (Table 9). In addition to trisomy 21, other
viable autosomal and sex chromosome aneuploidies, i.e.
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 first meiotic division. This relationship has been
demonstrated in Down syndrome patients with trisomy 21.
Using DNA polymorphisms, the extra chromosome 21
was identified to be of maternal origin in over 90% of cases
and in approximately 80% of these cases nondisjunction
occurred during the first 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 effect 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 offspring due to 3:1 disjunction increases
with maternal age similarly to the risk pattern for trisomy
21. A maternal age effect 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
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9
Chromosomal Syndromes and Genetic Disease
Table 9 Maternal age incidence of Down syndrome in fetuses
and liveborns
Incidence
Maternal age (years)
15–19
20–24
25–29
30
33
34
35
36
37
38
39
40
45 and over
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
Modified from Thompson et al. (1991) Genetics in Medicine, 5th edn.
WB Saunders.
than 30 years of age than for those over 30. In this situation,
lack of a maternal age effect 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
specific aneuploidy or polyploid conditions is rare.
Recurrence risk for unbalanced offspring of carriers with
various structural rearrangements has been derived
empirically (Table 11). Relatively specific 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 offspring is 1–2%.
Carriers of balanced rearrangements are usually clinically normal but have an increased risk for producing
unbalanced offspring. Risk for unbalanced gametes or
segregation products depends upon location of chromosome breakpoints relative to the centromere and crossover
frequency. Since it is difficult theoretically to predict the
rate of unbalanced offspring 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 figures 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
Table 10 Maternal age and chromosome abnormalities detected at amniocentesis
Rate per 1000
Age
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
ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net
Chromosomal Syndromes and Genetic Disease
Table 11 Risks of unbalanced offspring for rearrangement
carriers
rearrangement, the recurrence risk is generally considered
to be negligible.
Type of rearrangement
Percentage
of unbalanced
offspring
Robertsonian translocations
14/21, female
14/21, male
13/14, both sexes
21/22, female
21/22, male
21/21 both sexes
10–15
2–5
1–2
10–15
1–2
100
Chromosome abnormalities contribute significantly to
genetic disease. This impact is seen in various human
populations in the effect on the fetus or individual directly
or in the ability to produce healthy offspring. Autosomal
abnormalities are generally more detrimental than sex
chromosome abnormalities. Abnormalities involving entire chromosomes or subtle microdeletions can result in
clinically abnormal syndromes.
6–12
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
2–5
5–7
2
5–10
2
Modified from Nora and Fraser (1993) Medical Genetics: Principles
and Practices, 4th edn. Lea and Febiger.
translocation is approximately 2%. It should also be
emphasized that the recurrence risk is substantially higher
if the parental rearrangement was originally ascertained
through a liveborn child with an unbalanced chromosome
rearrangement, since this identifies unbalanced chromosome complements that are compatible with survival to
term. In those cases involving a de novo structural
Summary
de Grouchy J and Turleau C (1984) Clinical Atlas of Human
Chromosomes, 2nd edn. New York: Wiley.
Gelehrter TD, Collins FS and Ginsburg D (1998) Principles of Medical
Genetics, 2nd edn. Baltimore, MD: Williams and Wilkins.
Harper PS (1988) Practical Genetic Counseling, 3rd edn. Boston, MA:
Wright.
Hassold TJ (1986) Chromosome abnormalities in human reproductive
wastage. Trends in Genetics 2: 105–110.
Mitelman F (ed.) (1995) An International System for Human Cytogenetic
Nomenclature recommendations of the International Standing Committee on Human Cytogenetic Nomenclature, Memphis, Tennessee, USA,
October 9–13, 1994 Basel, Switzerland: Karger.
Nora JJ, Clarke Fraser F, Bear J, Greenberg CR, Patterson D and
Warburton D (1993) Medical Genetics: Principles and Practices, 4th
edn. Philadelphia: Lea and Febiger.
Schreinemachers DM, Cross PK and Hook EB (1982) Rates of trisomies
21,18,13 and other chromosome abnormalities in about 20 000
prenatal studies compared with estimated rate in live births. Human
Genetics 61: 318–324.
Therman E and Sulsman M (1992) Human Chromosomes: Structure,
Behavior and Function, 3rd edn. New York: Springer.
Thompson MW, McInnis RR and Willard HF (1991) Genetics in
Medicine, 5th edn. Philadelphia: WB Saunders.
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Chromosomal Syndromes and Genetic Disease
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