Chromosomal Genetic Secondary article

Disease: Numerical Article Contents

. Meiotic Nondisjunction

Aberrations . Mitotic Nondisjunction

. Aneuploidy in Spontaneous Abortion and at Birth

Wendy P Robinson, University of British Columbia, Vancouver, Canada . Sex Chromosome Aneuploidies: XXX, XYY, XXY, X
. Autosomal Aneuploidies
Deborah E McFadden, University of British Columbia, Vancouver, Canada
. Polyploidy
. Chromosome Mosaicism
Numerical aberrations represent a significant proportion of chromosomal changes found
. Uniparental Disomy
in humans. These errors can occur in meiosis or mitosis and therefore be constitutive
(present in all cells) or mosaic (present in some cells). They represent a significant cause of
pregnancy loss as well as abnormalities found in livebirths.

Meiotic Nondisjunction poles, premature resolution of chiasmata (location where

Meiosis is the process by which a diploid cell (one with two homologous chromosomes exchange genetic material), or
copies of all distinct chromosomes) produces a haploid premature separation of sister chromatids (Hawley et al.,
gamete (oocyte or spermatocyte) containing a single copy 1994). Very little is known about the causes of nondisjunc-
of each chromosome. The normal product of meiosis in tion in humans but some data suggest that premature
humans is a gamete containing 23 chromosomes: 22 separation of chromatids may often be involved.
autosomes and a sex chromosome (X or Y). In human The vast majority of aneuploidy in humans is maternal
females meiosis I is initiated during fetal development, but in origin (i.e. due to an error present in the oocyte) and its
is not completed until some 20–40 years later when an egg
is released from a follicle during ovulation. Meiosis II is not
completed unless the egg is fertilized by a sperm. In Parental diploid cell
contrast, spermatogenesis occurs continuously after pub-
erty in males and it takes 9 weeks for a spermatogonium to
develop into mature sperm, with meiosis requiring only 24
days to complete.
Segregation of chromosomes in human meiosis is
remarkably error-prone and roughly 20% of oocytes and
a few per cent of spermatocytes are either aneuploid,
having a numerically unbalanced chromosome comple-
ment, e.g. 22 or 24 chromosomes, or diploid (46 chromo- Meiosis I
somes). This error rate is at least an order of magnitude
higher than seen in any studied experimental organism.
There is no explanation for this difference, but it could
possibly be related to longer duration of meiosis I in
humans. Some consequences of these errors to human
reproductive health are failure of implantation, early 1st 1st
polar body polar body
pregnancy loss and birth defects or developmental delay Meiosis II
in liveborns.
Chromosome nondisjunction is defined as the unba-
lanced segregation of chromosomes leading to aneuploidy
and may occur at meiosis I (when homologous chromo- 2nd 2nd
somes segregate to opposite poles) or at meiosis II (when polar body polar body
the two sister chromatids separate at the centromere and
segregate to opposite poles) (Figure 1). Nondisjunction in
experimental organisms has been shown to result from a Oocyte Oocyte
(a) (b)
variety of causes, including improper alignment of
chromosomes on the spindle, failure of spindle proteins Figure 1 (a) Normal maternal meiosis; (b) a nondisjunction error at
that serve to pull homologous chromosomes to opposite maternal meiosis I.

ENCYCLOPEDIA OF LIFE SCIENCES © 2002, John Wiley & Sons, Ltd. www.els.net 1
 Chromosomal Genetic Disease: Numerical Aberrations

Trisomic zygote

Somatic loss

Figure 2 High-resolution G-banded chromosomes from an individual

with a 47,XYY chromosome complement.

Trisomy UPD
incidence increases dramatically with maternal age
Mosaic blastocyst
(Hassold et al., 1996). The exceptions to this rule are with trisomic and diploid (UPD) cells
47,XYY (presence of an extra Y-chromosome) (Figure 2)
and 45,X (a missing sex chromosome), which are
predominantly due to paternal or postfertilization events.
The cause of the increase of nondisjunction with maternal
age is not known but the ovarian environment may become
compromised as a woman ages owing to poorer regulation
of hormone levels (Freeman et al., 2000). Nondisjunction
appears to increase only slightly or not at all with paternal
age (Martin and Rademaker, 1992).
As yet there is no evidence from population studies for a
significantly increased risk of having a second aneuploid
pregnancy in couples who have experienced one pregnancy
loss due to aneuploidy, once maternal age is accounted for
(Warburton et al., 1987). However, increased rates of Figure 3 How trisomy mosaicism may arise. The trisomy originated with
aneuploidy can be found in some carriers of balanced two maternal (red) and one paternal (blue) chromosome. Loss of a
structural rearrangements (e.g. robertsonian transloca- chromosome in a trisomic conceptus may lead to either biparental
tions) or mutations in genes affecting deoxyribonucleic inheritance or uniparental disomy (UPD) (as shown), whereby both
chromosomes have originated from the mother. The fetus may show both
acid (DNA) repair (e.g. Bloom syndrome) or in individuals trisomic and diploid cells or there may be selective elimination of the
found to be mosaic for a trisomy (e.g. trisomy 21 trisomic cells from the majority of fetal tissues.
mosaicism). Furthermore, some men experiencing inferti-
lity show a disruption of chromosome pairing and meiotic
arrest that consequently leads to low (oligospermia) to no mitotic cell divisions and thus lead to mosaicism, with the
(azoospermia) mature sperm. In such men the sperm that presence of both aneuploid and normal diploid cells within
are found may have a higher than expected rate of sex one individual. Mitotic nondisjunction occurring during
chromosome abnormalities and diploidy. the somatic cell divisions preceding meiosis in oogenesis or
spermatogenesis may lead to germline mosaicism, and
result in an increased rate of eggs or sperm with aneuploidy
for a specific chromosome. Mitotic errors occurring during
Mitotic Nondisjunction early development may lead to a mixture of abnormal and
normal cells in the developing embryo (Figure 3). The
Mitosis is the process by which somatic cells divide; it abnormal cells may be confined to placental tissues or be
involves the replication of chromatids followed by present in both placenta and fetus. It is also possible for loss
segregation of sister chromatids to opposite poles. of a supernumerary chromosome in a trisomic conceptus
Chromosome segregation errors may also occur during to occur, resulting in mosaicism between the progenitor

2

trisomic cell line and a derivative diploid cell. Although
balanced in chromosome number, the resulting diploid cell
may not be balanced in terms of parental contribution, as it
is possible for both chromosomes from the involved pair to
be derived from a single parent, a situation termed
uniparental disomy (UPD).
Aneuploidy in Spontaneous Abortion
and at Birth
Based on rates of aneuploidy in gametes, over 20% of all
conceptions are expected to be aneuploid (Hassold et al.,
1996); however, it is estimated that more than half of these
fail to implant in the mother’s uterus and therefore do not
result in a detectable pregnancy. In particular, monosomy
(45 chromosomes in total, with one ‘missing’ chromosome)
for all autosomes and trisomy (47 chromosomes in total,
with one ‘extra’ chromosome) involving chromosomes 1, 3,
6, 11 and 19 are almost never observed among spontaneous
abortions and probably occur at conception but do not
persist beyond implantation (Figure 3).
Even when implantation is successful, the majority of
aneuploid pregnancies end in spontaneous abortion
(miscarriage). Chromosome errors thus account for about
half of pregnancy losses, with most occurring in the first
trimester of pregnancy. The most common abnormalities
found in spontaneous abortions are trisomy for chromo-
some 16, triploidy (69 chromosomes in total, consisting of
three complete haploid sets) and X-monosomy. Each of
these abnormalities accounts for approximately 6–8% of
all abortuses. However, trisomy for many other chromo-
somes, tetraploidy (92 chromosomes) and structural
rearrangements may also be observed. Strongly influenced
by maternal age, trisomy is estimated to affect less than 3%
of clinically recognized pregnancies in women aged 25
years but 35% of pregnancies in women aged 42 years.
Only a few abnormalities can survive to term in an
apparently nonmosaic state. These include trisomy 21,
trisomy 13, trisomy 18, triploidy and sex chromosome
aneuploidy, with a combined incidence of 1 per 300
livebirths. Stillbirths (infant born dead at or after 20 weeks
gestational age) are relatively rare (0.5–1 per 1000 births)
and are estimated to be aneuploid in 4% of cases. Many
abnormalities can survive to term in a mosaic state,
however it is difficult to assess how often this may occur, as
it is often impossible to diagnose.
Sex Chromosome Aneuploidies: XXX,
XYY, XXY, X
Sex chromosome aneuploidies are relatively common,
both because they occur more frequently and because they
Chromosomal Genetic Disease: Numerical Aberrations
are less likely to be aborted than other aneuploidies. The
most common are 45 chromosomes with a single X-
chromosome (45,X) or 47 chromosomes with either an
extra X or extra Y (47,XXX; 47,XXY or 47,XYY). The
presence of even four or five sex chromosomes (e.g.
48,XXYY; 49,XXXXX, etc.) has also been observed. Sex
chromosome abnormalities may also be mosaic with a
normal 46,XX or 46,XY cell line, which is expected to
make any potential abnormal effects milder. In a normal
female with two X-chromosomes, inactivation of the
majority of genes on one of the X-chromosomes occurs
in all somatic cells. The abnormal features involved in a
45,X individual are therefore attributable to loss of the
subset of genes that do not normally undergo X-chromo-
some inactivation. Likewise, in abnormalities involving an
excess of X-chromosomes, all Xs in excess of one undergo
X-chromosome inactivation. Thus the abnormal features
may be predominantly associated with an excess of those
genes that escape inactivation.
45,X (Turner syndrome)
45,X is a common cause of early pregnancy loss,
accounting for about 7% of spontaneous abortions. Based
on the liveborn frequency of 45,X (also called Turner
syndrome) of 1–2/10 000, it is estimated that less than 1%
of 45,X conceptuses will survive to term. About 30% of
Turner syndrome patients are mosaic, with both a 45,X cell
line and either a 46,XX cell line or one containing a
rearranged X-chromosome (Hook and Warburton, 1983).
Another 16% result from a nonmosaic structural abnorm-
ality of the X, including isochromosomes for the long arm
of the X-chromosome, ring X and short-arm deletions. The
phenotype in a liveborn infant is relatively mild, consider-
ing the high embryonic lethality, and it has been
hypothesized that possibly all liveborn females with Turner
syndrome carry a cell line containing two sex chromo-
somes, but it may be confined to a specific tissue (e.g. the
placenta) or be too low frequency to detect. Molecular
studies show that the single X-chromosome is maternally
derived in about 80% of 45,X cases. This is probably a
consequence of greater pairing problems between the X-
and Y-chromosome during male meiosis, as well as
perhaps a greater tendency to somatic loss of a Y-
chromosome as compared with an X-chromosome.
Diagnosis may be made in childhood, but is sometimes
not made until adolescence when the patient may be
investigated for unexplained short stature or primary
amenorrhoea. Features of Turner syndrome present in the
newborn include redundant neck skin and peripheral
lymphoedema (Linden et al., 1996). Congenital heart
disease, particularly coarctation of the aorta and atrial
septal defect, is present in 20%. There is an increased risk of
otitis media, adrenal anomalies, hypertension, autoim-
mune thyroid disease, and obesity. Y-chromosome or
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 Chromosomal Genetic Disease: Numerical Aberrations
Y-derived material is detectable in 6–9% of Turner
syndrome patients and is associated with an increased risk
of gonadoblastoma. Proportionate short stature is appar-
ent from childhood but may become particularly pro-
nounced during adolescence, with adult heights typically
ranging between 130 and 160 cm. Peripheral lymphoedema
occurs in about 40% of patients. Other clinical signs
include a broad chest, low posterior hairline, webbed neck,
hypoplastic nails and multiple pigmented naevi. Although
usually intellectually normal, 45,X girls show reduced
average intelligence level, with visuospatial construction
being affected more than verbal comprehension and
reading abilities.
The gonads of Turner syndrome women appear as
fibrous streaks, resulting in failure of secondary sexual
development and infertility. Hormone replacement ther-
apy may help achieve the development of normal female
sexual characteristics and prevent cardiovascular compli-
cations and osteoporosis in later life. Only a few per cent of
patients can become pregnant spontaneously (presumably
only when 46,XX cells exist in the ovaries). However,
oocyte donation has been successfully used as a treatment
option for infertility in these women.
47,XXX, 47,XYY and 47,XXY
47,XXX, 47,XXY and 47,XYY each occur in about 1/2000
livebirths. Approximately 50% of pregnancies carrying a
47,XXY complement end in spontaneous abortion, but
there does not appear to be an increased loss rate for
47,XXX or 47,XYY. There are no obvious clinical findings
at birth for any of these aberrations. On average there is a
slight deficit in cognitive abilities, but there is also a wide
spectrum of intelligence quotient (IQ) scores and the
majority of affected individuals are not mentally retarded.
Similarly, despite attempts in the literature to define a
psychological profile of these patients, there is clearly a
wide range of behaviours with no characteristics specific to
any syndrome (Linden et al., 1996).
47,XXX females are phenotypically normal, but may
tend to be taller than average. Early delays, particularly in
speech and language development, may be noted. 47,XXX
females have been reported to have impaired scores on tests
of concept formation, spatial thinking and verbal fluency.
Large numbers of patients have not been prospectively
studied, but it appears that the majority of 47,XXX women
can function reasonably well and become self-sufficient as
adults. In addition, the majority of affected females are
fertile and produce chromosomally balanced offspring.
Most nondisjunction errors leading to 47,XXX occur in
maternal meiosis I.
47,XXY (Klinefelter syndrome) is the most common
cause of hypogonadism and male infertility, accounting for
about 10% of infertile men. There is an increased
frequency of a variety of nonspecific major and minor
4
congenital abnormalities at birth. Clinodactyly is the most
common minor anomaly, being found in about 20% of
cases. The testes are small and fail to produce normal adult
levels of testosterone, which consequently leads to poorly
developed secondary male sexual characteristics as well as
gynaecomastia (breast development). Klinefelter males
have an increased incidence of learning disabilities, such as
reading deficiencies, poor spelling, speech and language
delays. However, overall IQ is on average only slightly
decreased. Height percentile tends to increase with age and
there may be poor gross motor coordination. Klinefelter
males have been reported to be at increased risk of diabetes,
osteoporosis, breast cancer, germ cell tumours and
leukaemias. The additional sex chromosome may be either
maternal or paternal in origin and in each cell two X-
chromosomes will be inactivated. About 15% are mosaic,
46,XY/47XXY. Molecular studies of sperm from oligos-
permic Klinefelter males show a significant increase of
both sex chromosome and autosomal abnormalities.
Nonetheless, the majority of sperm had a single sex
chromosome and ICSI (in vitro fertilization using intracy-
toplasmic sperm injection) has been successfully used to
produce offspring of Klinefelter males.
47,XYY may arise from a meiosis II error in the father or
a postfertilization mitotic event. There is no association
with increased parental age. Fertility and appearance is
normal but affected males tend to be taller than other
family members. Molecular studies on sperm from XYY
males suggest that the extra Y-chromosome is eliminated
during spermatogenesis in the majority of cells; however,
there is a slight increase in the frequency of aneuploid
sperm. Early reports suggesting that XYY males had a
tendency to aggressive and criminal behaviour were
controversial owing to biased ascertainment schemes.
More recent studies suggest that possible behavioural
problems may be attributable to those cases with a reduced
IQ rather than an increase in testosterone level or other
effects of an imbalance in sex chromosome gene expres-
sion. Nonetheless, although speech delay is common, IQ is
generally not reduced (Linden et al., 1996).
Autosomal Aneuploidies
Down syndrome (trisomy 21)
Trisomy 21 (Down syndrome) is the most common
chromosomal abnormality amongst livebirths, with an
incidence of 1/800. It is estimated that 80% of all trisomy
21 pregnancies conceived end as spontaneous abortions or
as stillbirths; approximately 2% of spontaneous abortions
and 1% of stillbirths will have trisomy 21. The majority of
trisomy 21 is due to a nondisjunction event; however,
approximately 4% of cases are associated with chromoso-
mal translocations, some of which are familial. The

observed frequency of trisomy 21 at 16 weeks gestation (the
time of amniocentesis) by maternal age is 1/1000 at age 25,
1/300 at age 35 and 1/22 at age 45. Mosaicism for trisomy
21 can occur in one of the two parents in a small percentage
of cases. Such couples would be expected to have an
increased risk of having additional trisomy 21 offspring,
although families with recurrent trisomy 21 are rare.
Trisomy 21 in the fetal period (more than 8 weeks
developmental age) shares some of the phenotypic features
seen in infants, including the dysmorphic facial features
(although usually less distinctive), cardiac anomalies
(characteristically atrioventricular canal defect) and duo-
denal atresia. Additionally, trisomy 21 fetuses may present
with generalized oedema (hydrops), the mechanism of
which is unclear. Many of these abnormalities can be
detected on ultrasound performed at 17–18 weeks gesta-
tion.
Most infants and children with trisomy 21 have a
distinctive dysmorphic facial appearance, with a flattened
facial profile and occiput, flattened nasal bridge, upslant-
ing palpebral fissures and protruding tongue. They may
also have single palmar (simian) creases, cardiac anomalies
and duodenal atresia. Children with trisomy 21 syndrome
are mentally retarded. They are at increased risk for
myeloproliferative disorders, including congenital leukae-
mia (transient myeloproliferative disorder) and leukaemia
later in life. The risk of Alzheimer dementia is also
increased, with onset much earlier than in the chromoso-
mally normal population.
Prenatal diagnosis for chromosome abnormalities, such
as trisomy 21, can be performed using chorionic villus
sampling (sampling from the placenta performed at 10–12
weeks gestation) or amniocentesis (performed at approxi-
mately 17 weeks gestation). In addition, the majority of
pregnancies at high risk of Down syndrome can be
identified based on a combination of ultrasound findings
at 17–18 weeks gestation and/or abnormal results of a
‘triple screen’. The triple screen measures the ratios of a-
fetoprotein (AFP), human chorionic gonadotropin (HCG)
and free oestriol in maternal blood; this ratio may be
altered in a characteristic pattern in Down syndrome
pregnancies and can thus assist in identifying at-risk
pregnancies. The test is most useful when the mother is
under 35 years of age.
Trisomy 13
Trisomy 13 is present in approximately 1/25 000 liveborn
infants. This represents only 1–2% of all trisomy 13
conceptuses, i.e. approximately 98% end either as sponta-
neous abortions or as stillbirths. Even when liveborn,
trisomy 13 is considered a lethal condition and most
affected persons die in early infancy. The trisomy 13
phenotype is characterized by a range of brain abnormal-
ities, including absence of the corpus callosum and
Chromosomal Genetic Disease: Numerical Aberrations
holoprosencephaly. Facial abnormalities are present and
mirror the extent of the forebrain abnormalities. Thus,
there may be microphthalmia and hypotelorism or
cyclopia. Bilateral cleft lip and palate are common. There
are often extra digits on the ulnar side of the hand. Cardiac
abnormalities are frequent and can include truncus
arteriosus and tetralogy of Fallot. Intrauterine growth
retardation is present in about half of infants with trisomy
13. Approximately 80% of trisomy 13 is due to non-
disjunction, with the majority of those (80%) the result of
maternal meiotic error. About 20% of cases are the result
of translocations, some of which are inherited.
Trisomy 18
Trisomy 18 syndrome is more common in livebirths than is
trisomy 13 but is still rare, occurring in 1/8000–10 000
livebirths. As with the other autosomal trisomies, the
majority of trisomy 18 conceptuses (95%) end as early
spontaneous abortions and, occasionally, as stillbirths.
Approximately 1% of spontaneous abortions and 1% of
stillbirths will have trisomy 18.
Infants with trisomy 18 are often growth-retarded. As
with other chromosome abnormalities, this is manifest on
prenatal ultrasound examination as symmetric growth
retardation. Affected infants have a small, triangular-
shaped face with small palpebral fissures, and there may be
mild retrognathia. The hands are characteristically held in
a fist, with the second and fifth fingers overlapping the third
and fourth, respectively. The feet may show a ‘rocker
bottom’ appearance with a prominent heel and a rounded
sole. Omphalocele and defects in the diaphragm are
common abnormalities. Almost all hearts will have
dysplastic cardiac valves, with thickened and rendundant
valve leaflet tissue. Abnormalities of the genitourinary
system are frequent and include glomerulocystic change,
hydronephrosis and bicornuate uterus. Survival beyond a
few months after birth is rare. Trisomy 18 most often arises
due to an error in maternal meiosis II, although meiosis I
and somatic errors may also be observed.
Polyploidy
Polyploidy refers to the presence of one or more extra
complete haploid sets of chromosomes. In humans,
triploidy (three haploid sets) is more common than
tetraploidy (four haploid sets).
Triploidy
Triploidy is estimated to be present in 1% of all clinically
recognized pregnancies, with 6% of spontaneous abor-
tions and 0.5% of stillborn infants affected. The extra
haploid set of chromosomes in triploidy may come from
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 Chromosomal Genetic Disease: Numerical Aberrations

either the mother (digynic) or father (diandric). Early are severely developmentally delayed and show a wide
studies suggested that 80% of triploidy was paternal in variety of anomalies. However, there does not appear to be
origin and usually the result of fertilization of an egg by two a distinct tetraploid phenotype. Survival is severely
sperms (dispermy). More recent studies show that 80–90% compromised, with infants usually dying within months
of fetal and later gestation triploidy is maternal in origin, of birth. Analysis of sex chromosome ratio from the small
with errors occurring in both the first and second meiotic number of reported cases suggests that most liveborns are
divisions (McFadden and Langlois, 2000). In addition, the result of postfertilization cleavage errors.
digyny accounts for more of the early triploid spontaneous
abortions than previously thought. Unlike most trisomies,
a maternal age effect has not been noted with triploidy,
even among those of maternal origin.
Chromosome Mosaicism
In the fetal period, the placental and fetal phenotypes
Chromosome mosaicism, mostly involving trisomy, is
correlate with the parental origin of the extra chromo-
detected in 1–2% of pregnancies undergoing chorionic
somes; in the embryonic period, the placental appearance
villus sampling and in 0.1% of amniocenteses. This
does. This difference in phenotype dependent on parental
difference reflects both the fact that some abnormal
origin of the chromosomes provided some of the first
pregnancies will be lost between the time of chorionic
evidence for imprinting effects in humans. Imprinting is
villus sampling and amniocentesis, and that a greater
defined as a difference in gene expression dependent on
number of mosaic abnormalities are detected by placental
parental origin. The digynic fetal phenotype is that of
sampling. Most often this mosaicism involves one chro-
severe asymmetric growth retardation with marked wast-
mosomally normal and one abnormal cell line. For
ing of the trunk and limbs and relative macrocephaly.
abnormalities compatible with life, such as trisomy 21 or
Characteristically, there is complete soft-tissue syndactyly
sex chromosome aneuploidy, the presence of a normal cell
of the third and fourth fingers and marked adrenal
line typically results in a less severe phenotype. When
hypoplasia. Other abnormalities are commonly found,
mosaicism involves a normally lethal abnormality, such as
including: central nervous system abnormalities such as
trisomy 16, the pregnancy may be ‘rescued’ by the diploid
encephaloceles and meningomyelocele, cleft lip and palate,
cell line and continue to term. In such cases the trisomic
gonadal hypoplasia, genital ambiguity or hypoplasia,
cells are typically found predominantly in placental tissue,
nonspecific cardiac abnormalities, and renal agenesis or
while most or all fetal tissues will carry the normal diploid
hypoplasia. The placenta is extremely small; no consistent
cell line. Outcome is usually normal, but there is an
histological abnormalities are present. The phenotype of
increased risk of intrauterine growth restriction, fetal
diandric triploidy differs in that the fetuses are less growth-
malformations and late fetal demise. Clinical outcome is
retarded and symmetrically so; thus, the head is in
strongly dependent on the involved chromosome and the
proportion to the rest of the body and truncal wasting is
level of trisomic cells in both placenta and fetus. Although
absent. These fetuses exhibit the same congenital anoma-
the presence of trisomic cells in amniotic fluid normally
lies as the digynic triploids but do not have adrenal
reflects the presence of trisomic cells in the fetus, the true
hypoplasia. The placenta may be abnormally large and
level and distribution of trisomic cells cannot be accurately
some placentas show changes of partial hydatidiform mole
assessed prenatally and ultrasound is often the best
(PHM), which is characterized by oedematous placental
predictor of fetal development.
villi and irregular growth of the placental trophoblast.
PHM is attributed to overrepresentation of the paternal
genome.
Uniparental Disomy
Tetraploidy Cells with UPD may have a numerically balanced
chromosome complement but are unbalanced in terms of
Tetraploidy is most often seen in early spontaneous parental contribution. This may arise by: (1) gamete
abortions, accounting for approximately 2.5% of them. complementation: an egg with an extra chromosome is
Tetraploidy occurs either as the result of a postfertilization fertilized by a sperm which was missing that same
cleavage error (with resultant XXXX or XXYY sex chromosome (or vice versa); (2) trisomic rescue: loss of a
chromosome complements) or as the result of trispermic supernumerary chromosome from a trisomic conceptus
fertilization of an ovum (with resultant XXXX, XXYY, (Figure 3); (3) compensatory UPD: an abnormal or missing
XXXY or XYYY sex chromosome complements). Some chromosome is replaced with a copy of the normal
show changes of PHM, which may usually be due to homologue (Robinson, 2000). There may be regions for
trispermic fertilization, but this finding has also been which sequences from both homologues have been
reported in postmitotic origin tetraploids. Rarely, liveborn transmitted (heterodisomy) or regions for which two
infants with tetraploidy have been reported. These infants identical copies have been transmitted (isodisomy) are

6

observed. Isodisomy can lead to transmission of two copies
of a recessive mutation from a heterozygous carrier parent.
UPD (either heterodisomy or isodisomy) can also cause
abnormalities as a consequence of genomic imprinting.
Imprinting, the differential expression of certain genes
dependent on parent of origin, has thus far been implicated
in several syndromes such as Prader–Willi syndrome
(UPD15mat), Angelman syndrome (UPD15pat), Beck-
with–Wiedemann syndrome (UPD11p15.5pat), transient
neonatal diabetes (UPD6pat), and Russell–Silver syn-
drome (UPD7mat) (Ledbetter and Engel, 1995). UPD
testing is usually recommended if trisomy mosaicism for
chromosome 7 or 15 is identified prenatally (trisomy for
chromosome 6 or 11 rarely occurs).
References
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with a reduced ovarian complement may have an increased risk for a
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Chromosomal Genetic Disease: Numerical Aberrations
McFadden DE and Langlois SL (2000) Parental and meiotic origin of
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Martin RH and Rademaker AW (1992) A study of paternal age and sex
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Further Reading
Dimmick J and Kalousek D (1992) Developmental Pathology of the
Embryo and Fetus. Philadelphia, PA: Lippincott.
Eggermann T, Nothen MM, Eiben B et al. (1996) Trisomy of human
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