Chromosomal Syndromes Introductory article

and Genetic Disease . Introduction

Article Contents

Frederick W Luthardt, Swedish Hospital Medical Center, Seattle, Washington, USA . Chromosome Abnormalities

Elisabeth Keitges, Dynacare Northwest, Seattle, Washington, USA . Outline of Chromosome Syndromes
. Maternal Age Effects
. Recurrence Risks
The normal human chromosome complement consists of 46 chromosomes comprising 22
. Summary
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 Figure 1 (Down syndrome karyotype with trisomy 21), or to

With the discovery in 1956 that the correct chromosome the absence of a single chromosome, or monosomy, as seen
number in humans is 46, the new era of clinical cytogenetics in Figure 2 (Turner syndrome karyotype with 45,X).
began its rapid growth. During the next few years, several The most common clinically significant chromosome
major chromosomal syndromes with altered numbers of abnormalities involving aneuploidy are frequently de-
chromosomes were reported, i.e. Down syndrome (trisomy tected in newborns (Table 1). Although autosomal and sex
21), Turner syndrome (45,X) and Klinefelter syndrome chromosome trisomies result in clinical abnormalities they
(47,XXY). Since then it has been well established that are more viable than monosomies, with the exception of
chromosome abnormalities contribute significantly to monosomy X (45,X Turner syndrome). However, fewer
genetic disease resulting in reproductive loss, infertility, than 5% of 45,X conceptions actually survive to birth.
stillbirths, congenital anomalies, abnormal sexual devel- Aneuploidy is frequently associated with maternal age and
opment, mental retardation and pathogenesis of malig- constitutes a significant portion of chromosome abnorm-
nancy. Specific chromosome abnormalities have been alities observed in spontaneous abortions (Table 2) and
associated with over 60 identifiable syndromes. They are detected prenatally in fetuses (Table 3).
present in at least 50% of spontaneous abortions, 6% of Polyploidy resulting from triploidy (69 chromosomes)
stillbirths, about 5% of couples with two or more or tetraploidy (92 chromosomes) are lethal conditions
miscarriages and approximately 0.5% of newborns. In most frequently seen in spontaneous abortions and very
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.

Chromosome Abnormalities
Numerical abnormalities
Chromosome abnormalities are classified as either numer-
ical 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 Figure 1 47,XX, 1 21 female Down syndrome karyotype demonstrating
copy of a specific chromosome, or trisomy, as seen in trisomy 21. (Karyotype prepared by Dave McDonald.)

ENCYCLOPEDIA OF LIFE SCIENCES © 2001, John Wiley & Sons, Ltd. www.els.net 1
 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. Structural abnormalities in infants (autosomes and sex
(Karyotype prepared by Dave McDonald.) chromosomes)
Balanced rearrangements
rarely in newborns with a short survival time. Triploidy is
Robertsonian 1/1120 live births
more common and is related to abnormal events prior to or Other 1/965
during fertilization: most often triploidy results from two Unbalanced rearrangements 1/1675
haploid sperm fertilizing a single haploid egg. Total 1/395
Aneuploid and normal diploid cells can occasionally
exist simultaneously in an individual. This condition is All chromosome abnormalities 1/160 live births
known as mosaicism and involves two or more distinct cell (autosomes and sex chromosomes)
populations derived from a single zygote or fertilized egg. Modified from Thompson et al. (1991) Genetics in Medicine, 5th edn.
Mosaicism can involve either autosomal or sex chromo- WB Saunders.
somes 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 Table 2 Relative frequencies of different abnormalities in
with Turner syndrome. The clinical significance of mosai- chromosomally abnormal spontaneous abortions
cism depends upon the proportion and tissue distribution Abnormality Percentage
of the aneuploid cells. Chimaerism, in contrast, is
distinguished from mosaicism in that the different cell Trisomies 52
lines are derived from more than one zygote. 45,X 18
Triploidy 17
Translocations 2–4
Structural abnormalities Modified from Harper (1988) Practical Genetic Counselling, 3rd edn.
Wright.
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 consists of two identical sister chromatids joined at the
‘q’ (Figure 3a). Chromosomes are metacentric when the centromere. Chromosomes normally have one centromere.
centromere is in the middle with short and long arms of A dicentric chromosome has two centromeres (Figure 3l)
roughly equal length (Figure 3i), submetacentric when the and an acentric chromosome has none. At metaphase,
centromere is closer to one end with short and long arms of when chromosomes are typically examined, sister chro-
unequal length (Figure 3a), and acrocentric when the matids appear fused as a result of the staining method
centromere is near one end with very small short arms necessary to produce the banding patterns essential for
(Figure 3l). The centromere is essential for correct segrega- chromosome identification (Figures 1 and 2). Each band
tion of chromosomes during cell division. DNA replication and subband has an assigned designation that identifies the
prior to cell division ensures that each chromosome 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 or unbalanced if there is either a gain (partial trisomy) or
Nomenclature (Figure 3a). Banding patterns are necessary loss (partial monosomy) of chromosome material.
to identify specific structural rearrangements within or The frequency of structural abnormalities varies con-
between different chromosomes. siderably in different populations. The highest frequency is
Structural rearrangements involve chromosome break- in spontaneous abortions and the lowest in newborns
age and reunion within a single chromosome or between (Table 4). This reduction can, in part, be explained by fetal
two or more different chromosomes resulting in either losses prior to birth, particularly in those cases with
balanced or unbalanced karyotypes. Rearrangements are significant unbalanced rearrangements.
balanced if there is no net change in chromosome material

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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 Spontaneous Prenatal
rearrangement abortions (%) diagnosis (%) Newborn (%)
0.4 0.2
冧
Balanced
2–4
Unbalanced 0.11 0.05
Data from various sources.

possible, though less likely, mechanism. The most common

Unbalanced rearrangements isochromosome involves the long arm of the X-chromo-
Unbalanced rearrangements usually result in significant some which is frequently seen in individuals with Turner
clinical abnormalities due to loss, duplication or both (in syndrome. Most X-isochromosomes are actually dicentric.
some cases) of genetic material. Some examples of Inactivation of one centromere makes this abnormal
unbalanced rearrangements are deletions, duplications, chromosome more stable during cell division. Autosomal
rings and isochromosomes (Figure 3). isochromosomes also occur and most frequently involve
Deletions result in loss of chromosome material from a acrocentric chromosomes with loss of their short arms.
single chromosome. Terminal deletions result from a single Unbalanced isochromosomes are always associated with
break within one chromosome arm with loss of material clinical abnormalities owing to their inherent genetic
distal to the break (Figure 3b). Interstitial deletions involve imbalance.
two breaks within the same chromosome arm with loss of
the material between the breaks (Figure 3c). Ring chromo-
Balanced rearrangements
somes are formed by breaks occurring in each chromosome
arm with loss of material distal to the breaks and with Carriers of balanced chromosomal rearrangements are
subsequent rejoining of the broken ends (Figure 3i). Ring usually clinically normal if no essential chromosome
chromosomes vary in size depending upon how much material is lost and no genes are damaged by the breakage
material has been lost. They are often unstable during cell and reunion process. However, they can produce unba-
division and can, very rarely, be transmitted from parent to lanced gametes and have an increased risk for chromoso-
offspring. mally abnormal offspring. Balanced rearrangements
Duplication of a chromosome segment usually occurs by include inversions, insertions, reciprocal translocations
unequal crossing over between homologous chromosomes and Robertsonian translocations (Figure 3).
or sister chromatids (Figure 3f). Duplications can also result Inversions are rearrangements within a single chromo-
from abnormal meiotic segregation in a translocation some resulting from two breaks with the intervening
(Figure 3k,l) or meiotic crossing over in an inversion segment being rotated 1808 prior to reconstitution.
(Figure 3d,e) carrier. In general, duplications are less Inversions are classified as either pericentric, which have
harmful than deletions but they inevitably are associated a single break in each arm (Figure 3d) or paracentric, which
with some clinical abnormalities. The degree of clinical have two breaks in one arm (Figure 3e). Pericentric
severity is correlated with size of the duplicated segment. inversions frequently produce a change in the relative
An isochromosome is a chromosome consisting of two arm lengths; paracentric inversions do not but can be
identical copies of one arm and none of the other (Figure 3h). identified by changes in the banding pattern of the
In a person with 46 chromosomes, an isochromosome chromosome arm affected. Inversion carriers are usually
results in partial monosomy and partial trisomy. Isochro- clinically normal but may have an increased risk for
mosomes most likely result from exchange between offspring with partial trisomy and monosomy. This is
homologues during meiosis, or from breakage and reunion because when chromosomes pair during meiosis an
of sister chromatids near the centromere. Centromere inversion loop is formed when the inverted segment pairs
misdivision during meiosis II is also considered to be a 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 recombi- cases approximately 80% are due to an error during
nants with duplication and deficiency of chromosome meiosis I. About 4% of Down syndrome patients have an
segments. The viability of these recombinant products is unbalanced Robertsonian translocation involving chro-
dependent upon the size of the unbalanced segments. mosome 21. Approximately 60% of these translocations
Recombinant chromosomes derived from paracentric involve the long arm of chromosome 13, 14, or 15 (most
inversions are typically acentric or dicentric and usually frequently chromosome 14). About half of these transloca-
result in nonviable offspring since these chromosomes are tions are de novo and half are inherited from a balanced
unstable during cell division. carrier parent (usually the mother). Nearly 40% of
Translocations result from the exchange of chromosome unbalanced Robertsonian translocations involve only
segments between two or more nonhomologous chromo- chromosomes 21 and 22. Most of these (
90%) involve
somes. There are three types of translocations: reciprocal, 21/21 long-arm fusions or isochromosomes and nearly all
Robertsonian and insertional. Reciprocal translocations are de novo. The rare parent who is a balanced 21/21
are produced by the exchange of broken-off segments isochromosome carrier has a 100% risk for having a viable
between two different chromosomes (Figure 3k). Carriers of offspring with Down syndrome. Female carriers of
balanced reciprocal translocations are usually normal but balanced 14/21 or 21/22 Robertsonian translocations have
they have an increased risk for unbalanced offspring. The a 10–15% risk for an unbalanced Down syndrome child.
actual risk is associated with segregation of the transloca- Male carriers have a risk of less than 5%. Mosaicism
tion components, position of breakpoints and centromere involving a mixture of normal diploid cells and trisomy 21
location. In general, viability is correlated with size of the cells is present in about 2% of Down syndrome patients.
unbalanced segment. Robertsonian translocations involve Trisomy 18 (Edwards syndrome) is the second most
two acrocentric chromosomes that join near their centro- common autosomal trisomy syndrome. It has a frequency
meres, to form a single chromosome (Figure 3l). Frequently, of about 1 in 8000 live births. Clinical features include
this single chromosome has two centromeres, resulting in a failure to thrive, cardiac and kidney problems and other
dicentric chromosome. Balanced Robertsonian transloca- congenital abnormalities (Table 5). Postnatal survival is
tion carriers have only 45 chromosomes including the poor and more than 90% die within the first 6 months.
dicentric chromosome. Carriers of balanced Robertsonian About 80% are female. The incidence of trisomy 18
translocations are usually clinically normal but have an increases with maternal age. Very few cases of trisomy 18
increased risk of unbalanced offspring. This risk is higher mosaicism have been reported. Many features character-
for female carriers since males frequently have infertility istic of trisomy 18 have also been reported in patients with
problems. An insertional translocation is the result of three unbalanced translocations involving all or most of
breaks such that a nonreciprocal change occurs when the chromosome 18 long arm. Based upon limited data, the
segment from one chromosome is inserted into another recurrence risk for trisomy 18 is approximately 1%.
chromosome (Figure 3j). Insertions are relatively rare since Trisomy 13 (Patau syndrome) is the least common of the
they involve three breaks. Insertion carriers are clinically major autosomal trisomies with an estimated incidence of 1
normal but have an increased risk for offspring with partial in 20 000 live births. Owing to severe clinical abnormalities
monosomy or partial trisomy for the inserted segment. including central nervous system malformations, heart
defects, growth retardation and numerous other congeni-
tal anomalies (Table 5), trisomy 13 patients rarely survive
the newborn period. Trisomy 13 is associated with
Outline of Chromosome Syndromes advanced maternal age. The extra 13 usually results from
a maternal meiotic nondisjunctional error. About 20% of
Common autosomal trisomies cases have an unbalanced Robertsonian translocation
involving chromosome 13. Balanced 13/14 Robertsonian
Trisomy 21 (Down syndrome) is one of the best-recognized translocation carriers have less than 2% risk of having an
and most common chromosome disorders. It is the single unbalanced trisomy 13 offspring. Trisomy 13 mosaicism is
most common genetic cause for mental retardation. The rare and may be associated with less severe clinical
incidence of Down syndrome is approximately 1/800 anomalies.
newborns. The risk for having a child with trisomy 21
Down syndrome increases with maternal age. Clinical
features include mental and growth retardation, charac- Common sex chromosome abnormalities
teristic facies and other abnormalities described in Table 5.
Approximately 94% of Down syndrome patients have Sex chromosome abnormalities have less severe clinical
trisomy 21 (Figure 1) resulting from meiotic nondisjunction, anomalies than those associated with comparable auto-
the failure of homologous chromosomes or sister chroma- somal imbalances. This difference can be attributed to
tids to separate during cell division. In about 95% of cases genetic inactivation of all but one X-chromosome in those
the extra chromosome 21 is of maternal origin, and of these 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 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
Edwards Trisomy 18 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
Patau Trisomy 13 Severe mental deficiency, small eyes, cleft lip and/or palate, extra fingers and toes,
cardiac anomalies, midline brain anomalies, genitourinary abnormalities
Turner 45,X Female with retarded sexual development, usually sterile, short stature, webbing of skin
in neck region, cardiovascular abnormalities, hearing impairment, normal intelligence
Klinefelter 47,XXY Male, infertile with small testes, may have some breast development, tall, mild mental
deficiency, long limbs, at risk for educational problems
Triple X 47,XXX Female with normal genitalia and fertility, at risk for educational and emotional
problems, early menopause
XXY 47,XYY 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 Klinefelter syndrome (47,XXY)
aneuploidy is relatively common, with overall frequency of Klinefelter syndrome has a frequency of about 1 in 1000
about 1 in 500 live births (Table 1). Some (XXX, XXY, newborn males (Table 1). Unlike Turner syndrome, males
XYY) are relatively frequent in newborns but rare in with Klinefelter syndrome are not usually detected in the
spontaneous abortions. Monosomy X (Turner syndrome),
newborn period. These individuals are generally normal in
in contrast, is one of the most common chromosome appearance before puberty. After puberty they are
abnormalities seen in spontaneous abortions but relatively
frequently ascertained in infertility clinics or identified by
rare in newborns. 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 educa-
tional and emotional problems. Most Klinefelter patients
have a 47,XXY karyotype. At least 10% have mosaicism
Turner syndrome (45,X)
involving normal 46,XY cells plus another population of
The frequency of Turner syndrome is about 1 in 8000 cells with two or more X chromosomes. Mosaic patients
newborn females. Clinical features in newborns often have more variable clinical features and occasionally may
include webbed neck, low hairline, puffy hands and feet, have relatively normal testicular development.
wide spaced nipples and cardiovascular problems. Later in Cytogenetic and molecular data have indicated that
life, these girls are typically short, sexually immature and 47,XXY is equally likely to result from a maternal or
infertile (Table 5). Slightly more than 50% of Turner paternal meiotic nondisjunctional error. Maternally de-
syndrome patients have a 45,X karyotype (Figure 2). The rived cases are associated with maternal age. Variants of
remaining Turner patients have other sex chromosome Klinefelter syndrome include those patients with more
abnormalities of the X-chromosome involving isochromo- than two X-chromosomes, multiple X-chromosome mo-
somes, short-arm deletions and rings. About 30% of saicism and multiple Y-chromosomes. The presence of
Turner patients are mosaics consisting of 45,X cells plus additional X-chromosomes (more than two) is associated
other cells with two or more normal X-chromosomes, with increasing severity of clinical abnormalities including
structurally abnormal X-chromosomes or a Y-chromo- mental retardation, sexual development and skeletal
some. anomalies.
Approximately 95–99% of 45,X conceptions fail to
survive to term and account for about 18% of chromoso-
mally abnormal spontaneous abortions. The incidence of 47,XYY syndrome
45,X is not associated with maternal age. The paternal X- Approximately 1 in 1000 newborn males have a 47,XYY
chromosome is missing in about 75% of 45,X patients. 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 cytogenetically, but occasionally it is too small and can
development is normal and they are fertile (Table 5). only be identified molecularly with specific DNA probes
Although most 47,XYY patients are clinically normal, utilizing FISH methods. Cri du chat syndrome is one of the
they tend to be taller than normal and have an increased earliest deletion syndromes to be described. It has an
tendency for behavioural and learning problems as incidence of about 1 in 50 000 births. The critical region has
children and young adults. Y-chromosome aneuploidy been mapped to 5p15.2. About 90% of deletions are de
results from paternal meiotic nondisjunction and is not novo and 10% are derived from an unbalanced familial
associated with maternal age. translocation. Langer–Giedion syndrome is a rare condi-
tion with microcephaly and mental retardation. The
Trisomy X syndrome (47,XXX) critical region has been assigned to 8q24.11-q24.13. A
The frequency of 47,XXX in newborn females is about 1 in cytogenetically visible deletion is seen in about 50% of
1000 (Table 1) and is associated with maternal age. Most cases.
XXX females are clinically normal with normal gonadal More recently, a group of autosomal microdeletions or
function and fertility. However, there is an increased risk contiguous gene syndromes have been identified that have
for learning disabilities, reduction in performance IQ, a consistent but complex phenotype associated with a very
menstrual problems and early menopause (Table 5). Fe- small (usually 5 5 Mb) chromosomal deletion. Although
males with more than three X-chromosomes (XXXX and some microdeletions are cytogenetically visible, the current
XXXXX) have been reported but, in comparison to method is to identify these syndromes by FISH utilizing
47,XXX, are quite rare. These tetra-X and penta-X females fluorescently labelled DNA probes specific for the deleted
are all mentally retarded and have more severe clinical segments. Some of the more common microdeletion
problems. 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
Autosomal deletion and duplication blood vessels, skin and other organs. The de novo deletion
syndromes is of maternal origin in 61% of cases and paternal in 39%.
Identification of common autosomal deletions requires Genomic imprinting, the differential expression of alleles
precise chromosomal localization of the missing segment. depending on the parent of origin, has been reported for
Chromosome banding patterns make this localization the maternal deletion group of Williams patients since they
possible if the deletion is cytogenetically visible. Detection had significantly more severe growth retardation and
of common deletions and also very small deletions not microcephaly than the paternal deletion group. Some
visible by routine cytogenetic analysis (microdeletions) has genes mapped to the WAGR critical region have also
been made possible by fluorescence in situ hybridization revealed genomic imprinting. The incidence for Prader–
(FISH) technology. This technique involves hybridizing Willi syndrome and Angelman syndrome is approximately
specific fluorescently tagged DNA probes to metaphase 1 in 10 000 births, respectively. About 60% of Prader–Willi
chromosomes, which are detectable by UV excitation. and Angelman syndrome patients have a cytogenetically
Absence of a locus-specific fluorescent probe from one visible deletion in the same region of chromosome 15.
homologue is indicative of a microdeletion. FISH analysis identifies a microdeletion in about 70% of
Several common autosomal deletion syndromes are cases of both syndromes. DNA polymorphism demon-
described in Table 6. The critical region for Wolf–Hirsch- strated that in Prader–Willi syndrome the deleted 15 was of
horn syndrome has been assigned to 4p16.3. In 90% of paternal origin and was of maternal origin in Angelman
cases the deletion is de novo and in 10% it is inherited as an syndrome patients. These observations suggested that the
unbalanced translocation. The deletion is usually visible difference in clinical features for patients with identical

Table 6 Common autosomal deletions

Syndrome Chromosome region deleted Main clinical features
Wolf–Hirschhorn 4p16.3 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
Cri du chat 5p15.2 High-pitched cry, wide-spaced eyes, small chin, small head, round face,
severe psychomotor and mental retardation
Langer–Giedion 8q24.11-q24.13 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 11p15.5. Fifteen per cent of cases are familial, due to
parental origin (genomic imprinting). About 30% of maternal carriers with translocations or inversions with a
Prader–Willi patients have two copies of maternal breakpoint on 11p. These female carriers are clinically
chromosome 15 and no paternal copy, a condition called normal but their offspring may have clinical effects
uniparental disomy (UPD). Fewer than 5% of Angelman suggesting a role for genomic imprinting. Cytogenetic
patients have paternal UPD for chromosome 15. A small abnormalities are present in 2–3% of Beckwith–Wiede-
proportion (1% Prader–Willi and 4% Angelman) have man patients. The most frequent abnormality is duplica-
neither deletions nor UPD but have abnormal methylation tion of 11p13!p15 resulting from the unbalanced
patterns (differential expression of imprinted genes) at loci segregation of a paternal translocation or inversion. De
in 15q11-q13 due to imprinting mutations. At least 20% of novo 11p15.5 duplications of paternal origin have also been
nondeletion, non-UPD 15, normally methylated and reported in some patients with Beckwith–Wiedeman
cytogenetically normal Angelman patients have other syndrome. Patients with duplication or trisomy for
genetic mutations. A visible cytogenetic deletion is seen 11p15.5 have a higher incidence of clinical abnormalities
in about 50% of Miller–Dieker syndrome patients. FISH than those with normal chromosomes. Charcot–Marie–
analysis identifies a microdeletion in 90% of all Miller– Tooth disease type 1A (CMT1A) is the most common
Dieker patients. Hemizygosity for an interstitial deletion of inherited peripheral neuropathy in humans and has a
chromosome 22q11.2 is associated with variable but prevalence rate of 1 in 2500. In most cases CMT1A patients
overlapping syndromes known as Catch 22, DiGeorge have normal chromosomes with duplication of DNA
syndrome and velocardiofacial syndrome. As a group, markers within 17p11.2!p12. A number of CMT1A
these syndromes have an incidence of about 1 in 5000 births patients have been reported with cytogenetically visible
and may account for 5% of all congenital heart defects. duplication of 17p11.2p12, demonstrating that this syn-
Cytogenetic deletions are seen in about 30% of these drome is correlated with a gene dosage effect for this
patients. FISH analysis is much more sensitive and chromosome region. Misalignment of homologous chro-
identifies 85–90% of patients with microdeletions. mosomes resulting in unequal crossing over between non-
Autosomal duplication syndromes are much less com- sister chromatids during meiosis is the most likely
mon than autosomal deletion syndromes. Several auto- mechanism for this type of de novo chromosome duplica-
somal duplication syndromes are described in Table 8. tion. Cat-eye syndrome results from duplication of the
Beckwith–Wiedeman syndrome has an incidence of 1 in proximal portion of the chromosome 22 long arm. The
13 700 births. Approximately 85% are de novo and 20– most common form of this duplication is a supernumerary
28% of these cases are due to paternal UPD for region (extra) dicentric bisatellited chromosome 22 designated as

Table 7 Autosomal microdeletion syndromes

Chromosome
Syndrome region Incidence Main clinical features
Williams 7q11.23 1/20 000 Cardiac anomalies, mental retardation, characteristic facies, growth
retardation, gregarious disposition, connective-tissue problems
WAGR 11p13 Kidney tumour, absence of iris, genital abnormalities, growth retardation
Prader–Willi 15q11.2 1/10 000 Developmental delay, mental retardation, decreased muscle tone, obesity,
small genitals, excessive appetite, hypopigmentation
Angelman 15q11.2 1/10 000 Developmental delay, mental retardation, unstable gait, absence of speech,
hyperactivity, spontaneous laughter, hypopigmentation
Miller–Dieker 17p13.3 Smooth brain, small head, small chin, growth failure, cardiac abnormalities
Smith–Magenis 17p11.2 1/25 000 Flat midface, wide head, broad nasal bridge, short fingers and toes, mental
retardation, hyperactivity, short stature, characteristic behavioural
problems
Alagille 20p11.23-p12.2 Chronic bile flow suppression, dysmorphic facies, ring-like corneal opacity,
vertebral arch defects, narrowing of heart opening
Catch 22 22q11.2 Cardiac defects, abnormal facies, underdeveloped thymus, cleft palate,
decreased calcium in blood
DiGeorge 22q11.2 1/5000 Underdeveloped thymus and parathyroid glands, facial abnormalities,
cardiac defects
Velocardiofacial 22q11.2 Cleft palate, abnormal nose, developmental delay, cardiac abnormalities
Data from various sources.

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 Chromosomal Syndromes and Genetic Disease

Table 8 Autosomal duplication syndromes

Chromosome
Syndrome region duplicated Main clinical features
Beckwith–Wiedemann 11p15.5 Large tongue, tissue and organ overgrowth, mild mental retardation
Charcot–Marie–Tooth 17p11.2-p12 Decreased reflexes, progressive distal muscular wasting, decreased
disease type 1A muscle tone, sensory neuropathy
Cat-eye 22pter-q11.2 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 trisomy 13, trisomy 18, XXX and XXY are also associated
requires breakage at 22q11.2 in each of two sister or non- with maternal age (Table 10).
sister chromatids and produces a chromosome containing Over 50% of chromosomally abnormal spontaneous
two copies of the cat-eye syndrome critical region abortions are trisomic for various chromosomes and, as a
(CESCR) or a total of four copies for the patient. These group, are more frequently associated with maternal age
patients typically have 47 chromosomes owing to the when compared to polyploid and nontrisomic abortions.
presence of the supernumerary inv dup(22)(q11.2). Other chromosomally abnormal spontaneous abortions
with sex chromosome monosomy (45,X), triploidy, tetra-
Chromosome instability syndromes ploidy and various other structural abnormalities are not
associated with maternal age.
There are several rare inherited syndromes characterized The risk for aneuploidy increases with maternal age
by increased rates of spontaneous or induced chromoso- primarily owing to meiotic nondisjunction errors asso-
mal breakage and predisposition to leukaemia and solid ciated with reduced recombination or crossing over prior
cancers. The most extensively studied of these syndromes, to the first meiotic division. This relationship has been
each caused by a different autosomal recessive gene, are demonstrated in Down syndrome patients with trisomy 21.
Bloom syndrome, Fanconi anaemia, ataxia telangiectasia Using DNA polymorphisms, the extra chromosome 21
and xeroderma pigmentosum. These syndromes have was identified to be of maternal origin in over 90% of cases
distinctive chromosome aberrations. Bloom syndrome is and in approximately 80% of these cases nondisjunction
characterized by quadriradial formations, which is the occurred during the first meiotic division. A similar
exchange of chromatid segments between two chromo- relationship implicating a higher frequency of maternal
somes, and a high rate of sister chromatid exchange (SCE) nondisjunction errors has also been reported for trisomy
or exchanges between homologous chromosome segments. 13, 16, 18, XXX and XXY.
Fanconi anaemia patients exhibit a high frequency of In addition to being associated with various aneuploid
chromosome breakage and nonhomologous chromosome syndromes, the maternal age effect has also been observed
interchange following exposure to alkylating agents or in cases involving structural rearrangements associated
ultraviolet radiation. Their SCE rate is normal. Individuals with nondisjunction and segregation errors. Data from
with ataxia telangiectasia show an increased level of some balanced translocation carriers indicate that the risk
chromosome breaks and rearrangements and may have for unbalanced offspring due to 3:1 disjunction increases
abnormalities involving chromosome 14. These patients with maternal age similarly to the risk pattern for trisomy
have a normal SCE level. Patients with xeroderma 21. A maternal age effect has also been reported for some de
pigmentosum do not exhibit spontaneous chromosome novo structural rearrangements, particularly those invol-
breakage; however, rearrangement, breaks, and increased ving bisatellited supernumerary marker chromosomes.
SCE rate are observed after exposure to ultraviolet In contrast to maternal age-related risk for aneuploidy,
radiation. 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
Maternal Age Effects similar to their age-related risk. The reason for the higher
recurrence risk in younger women is not known. In cases of
Prenatal and live birth risks for trisomy 21 Down familial Robertsonian translocations involving chromo-
syndrome are well established and are clearly associated some 21, the risk for an unbalanced Robertsonian
with maternal age (Table 9). In addition to trisomy 21, other translocation Down syndrome is higher for women less
viable autosomal and sex chromosome aneuploidies, i.e.

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 Chromosomal Syndromes and Genetic Disease

Table 9 Maternal age incidence of Down syndrome in fetuses

its origin (de novo or familial) and the sex of the carrier
and liveborns patient. The empirical recurrence risk for trisomy 21 for
parents with normal chromosomes is approximately 1%
Incidence and increases to 2% if the mother is aged 40 or over. This
At amniocentesis indicates that in younger women the recurrence risk is
Maternal age (years) At birth (16 weeks) increased over what is expected for their age, while in
15–19 1/1250 – women 35 years or older the risk is age-related. With the
20–24 1/1400 – exception of trisomy 21, the recurrence risk for other
specific aneuploidy or polyploid conditions is rare.
25–29 1/1100 –
Recurrence risk for unbalanced offspring of carriers with
30 1/900 –
various structural rearrangements has been derived
33 1/625 1/420 empirically (Table 11). Relatively specific risk estimates
34 1/500 1/325 are known for more common types of Robertsonian
35 1/350 1/250 translocations. The recurrence risk for an unbalanced
36 1/275 1/200 Robertsonian translocation Down syndrome child is
37 1/225 1/150 dependent upon which parent is the 14/21 or 21/22 carrier.
38 1/175 1/120 However, if a person is a 21/21 carrier, the recurrence risk is
39 1/140 1/100
100% regardless of which parent is the carrier. For carriers
of 13/14 Robertsonian translocation, the risk for an
40 1/100 1/75
unbalanced trisomy 13 offspring is 1–2%.
45 and over 1/25 1/20 Carriers of balanced rearrangements are usually clini-
Modified from Thompson et al. (1991) Genetics in Medicine, 5th edn. cally normal but have an increased risk for producing
WB Saunders. unbalanced offspring. Risk for unbalanced gametes or
segregation products depends upon location of chromo-
some breakpoints relative to the centromere and crossover
frequency. Since it is difficult theoretically to predict the
than 30 years of age than for those over 30. In this situation, rate of unbalanced offspring to be expected for any
lack of a maternal age effect can be attributed to knowledge particular structural rearrangement, risk estimates are
of being a translocation carrier and the impact of this based upon pooling of pregnancy outcome data from all
knowledge upon the decision to have more children. 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.
Recurrence Risks This translocation is often familial, with reduced fertility in
males. Unbalanced probands are nearly always born to
Recurrence risks for chromosomal abnormalities depend
carrier females. The recurrence risk for the unbalanced
upon the type of abnormality, i.e. numerical or structural,

Table 10 Maternal age and chromosome abnormalities detected at amniocentesis

Rate per 1000
All chromosome
Age Trisomy 21 Trisomy 18 Trisomy 13 XXX XXY anomalies
35 3.9 0.5 0.2 0.6 0.5 8.7
36 5.0 0.7 0.3 0.7 0.6 10.1
37 6.4 1.0 0.4 0.7 0.8 12.2
38 8.1 1.4 0.5 0.8 1.1 14.8
39 10.4 2.0 0.8 1.2 1.4 18.4
40 13.3 2.8 1.1 1.5 1.8 23.0
41 16.9 3.9 1.5 1.8 2.4 29.0
42 21.6 5.5 2.1 2.4 3.1 29.0
45 44.2 – – 18.0 7.0 62.0
Modified from Harper (1988) Practical Genetic Counselling, 3rd edn. Wright.

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 Chromosomal Syndromes and Genetic Disease

Table 11 Risks of unbalanced offspring for rearrangement rearrangement, the recurrence risk is generally considered
carriers to be negligible.

Percentage
of unbalanced
Type of rearrangement offspring
Summary
Robertsonian translocations Chromosome abnormalities contribute significantly to
14/21, female 10–15 genetic disease. This impact is seen in various human
14/21, male 2–5 populations in the effect on the fetus or individual directly
13/14, both sexes 1–2 or in the ability to produce healthy offspring. Autosomal
21/22, female 10–15 abnormalities are generally more detrimental than sex
21/22, male 1–2 chromosome abnormalities. Abnormalities involving en-
21/21 both sexes 100 tire chromosomes or subtle microdeletions can result in
Reciprocal translocations clinically abnormal syndromes.
Pooled, both sexes 6–12
Ascertained by unbalanced child 20 Further Reading
Ascertained by unbalanced child with 50
small unbalanced segment de Grouchy J and Turleau C (1984) Clinical Atlas of Human
Chromosomes, 2nd edn. New York: Wiley.
Other ascertainment 2–5
Gelehrter TD, Collins FS and Ginsburg D (1998) Principles of Medical
t(11;22)(q23;q11.2) 5–7 Genetics, 2nd edn. Baltimore, MD: Williams and Wilkins.
Recurrence risk unbalanced t(11;22) 2 Harper PS (1988) Practical Genetic Counseling, 3rd edn. Boston, MA:
Wright.
Pericentric inversions
Hassold TJ (1986) Chromosome abnormalities in human reproductive
Ascertained by unbalanced child 5–10 wastage. Trends in Genetics 2: 105–110.
Other ascertainment 2 Mitelman F (ed.) (1995) An International System for Human Cytogenetic
Nomenclature recommendations of the International Standing Commit-
Modified from Nora and Fraser (1993) Medical Genetics: Principles
and Practices, 4th edn. Lea and Febiger. tee 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.
translocation is approximately 2%. It should also be
Schreinemachers DM, Cross PK and Hook EB (1982) Rates of trisomies
emphasized that the recurrence risk is substantially higher 21,18,13 and other chromosome abnormalities in about 20 000
if the parental rearrangement was originally ascertained prenatal studies compared with estimated rate in live births. Human
through a liveborn child with an unbalanced chromosome Genetics 61: 318–324.
rearrangement, since this identifies unbalanced chromo- Therman E and Sulsman M (1992) Human Chromosomes: Structure,
some complements that are compatible with survival to Behavior and Function, 3rd edn. New York: Springer.
term. In those cases involving a de novo structural Thompson MW, McInnis RR and Willard HF (1991) Genetics in
Medicine, 5th edn. Philadelphia: WB Saunders.

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