Imprinting Diseases

Prader–Willi syndrome (PWS) and Angelman
syndrome (AS) are two distinct neurogenetic
developmental disorders that result from
different genetic lesions in a 3–4 Mb contiguous
region of human chromosome 15 (15q11–
13). This region is imprinted, i.e., genes on the
maternal or the paternal allele only are expressed.

Two syndromes associated with the same chromosomal region

Prader–Willi syndrome is characterized by
neonatal muscular weakness and feeding difficulties,
followed in early childhood by reduced
or lack of satiation control leading to massive
obesity in many patients. Several other, variable
features occur, such as mental retardation,
characteristic facial features, short stature, hypopigmentation,
behavioral problems, and
other findings. In Angelman syndrome the
developmental retardation is usually very
severe. Nearly total lack of speech development,
an abnormal electroencephalogram with tendency
to seizures, and hyperactivity are almost
always present.

Parental origin of the deletion

PWS results when the deleted chromosome involves
the chromosome 15 of paternal origin
(loss of one paternal allele 2 in the
diagram of a Southern blot on the left). AS results
when the deletion involves the chromosome
15 of maternal origin (loss of one maternal
allele 1 in the scheme on the right).

Uniparental disomy

Uniparental disomy (UPD) is the presence of
two chromosomes or genes from the same
parent. The diagram of a Southern blot shows
two different types of UPD in PWS: isodisomy
and heterodisomy. In isodisomy the two parental
alleles are identical (two maternal alleles 1
shown in the diagram). In heterodisomy the
two alleles are of the same parental origin, but
differ

Parent-of-origin deletion and uniparental disomy

A deletion and uniparental disomy have the
same functional result, i.e., loss of the genetic
activity of one parental allele. The frequency of
a deletion is about the same for PWS and AS
(70% each), whereas the frequency of UPD
differs considerably: 29% in PWS, 1% in AS.

Chromosomal region 15q11–13 and imprinting center

Five genes known to date are transcribed from
the paternal allele only, not from the maternal
allele where they are constitutively repressed
(blue squares). From the more distal gene
UBE3A (a ubiquitin-protein ligase E3) only the
maternal allele is transcribed. About 25% of
cases of Angelman syndrome are caused by
deletion or mutation of this gene. The breakpoints
of the common large deletions occur predominantly
in three breakpoint cluster regions.
The imprinting center (IC) was originally defined
by small deletions outside of the known
imprinted genes. About 1% of patients with
PWS and 4% with AS have imprinting center defects.
The imprinted region on 15q11–13 shows
a difference in methylation pattern between the
maternal and the paternal allele. This is the
basis of a diagnostic test.
(Data in E. kindly provided by Dr. Karin Buiting).
Other imprinted chromosomal regions are also
associatedwithhumandiseases, e.g.,Beckwith–
Wiedemann syndrome and some patients with
Russell–Silver syndrome, among others.

Karyotype – Phenotype Correlation

Autosomal Trisomies
A trisomy (the presence of three homologous
chromosomes instead of the usual two) arises
prezygotically during meiosis due to faulty distribution
(nondisjunction) of a chromosome
pair. Itmay also arise after fertilization (postzygotic)
during somatic cell division (mitosis); in
this case, trisomy is present in a certain proportion
of cells (chromosomal mosaicism). Trisomy
leads to a phenotype characteristic for the particular
chromosome, although in humans most
trisomies are lethal in early embryonic development.

Trisomy in jimsonweed (Datura stramonium)

In 1922, Blakeslee observed that triploid and
tetraploid jimsonweed plants (Datura stramonium)
differ little in phenotype. However,
when plants contained three copies of only one
of the 12 chromosomes (trisomy), and two each
of the others, a characteristic appearance resulted
for each of the trisomies

Trisomies in the mouse

During the 1970s, A. Gropp and co-workers investigated
the effect of trisomies on the
development of the mouse. Trisomic mice, resulting
from the segregation of translocations,
had a developmental profile and certain morphological
changes characteristic for each
trisomy (1). Embryos with a chromosome
missing (monosomies) died very early in gestation.
(Figure fromA. Gropp, 1982). Amouse embryo
with trisomy 12 shows an open skull cap
and other malformations on the 14th day of
development (2), unlike other embryos of the
same age (H.Winking, Lübeck, 1991; Boué et al.,
1985). Only trisomy 19 is compatible with survival
until birth (day 21), but the brain is too
small (3). These animals die shortly after birth.

Autosomal trisomies

Autosomal trisomies in man
Of the 22 autosomes in man, only three occur
regularly as trisomies in live-born infants:
trisomy 21, trisomy 18, and trisomy 13. They
differ in phenotype and course of disease. Other
trisomies are not observed in live-born infants
because they are lethal in early embryonic life,
and not compatible with life at birth (see
p. 402). Trisomy 21 causes the clinical picture of
Down syndrome (formerly called mongolism).

Nondisjunction as a cause of trisomy

Especially in trisomy 21, the frequency of nondisjunction
depends on the age of the mother at
the time of conception (1). The age of the father
has very little or no influence.
Nondisjunction may occur during the first or
the second maturation division (meiosis I or
meiosis II, p. 116) (2). The difference can be established
by appropriate chromosomal
markers. If nondisjunction occurs in meiosis I,
the three chromosomes will be different
(1 + 1 + 1), whereas if nondisjunction occurs
during meiosis II, two of the three chromosomes
will be identical (2 + 1). In humans, about
70% of nondisjunctions occur in meiosis I, and
30% in meiosis II.

Other Numerical Chromosomal Deviations

In addition to the autosomal trisomies, there
are other conditions associated with an abnormal
number of chromosomes. They involve
either the entire set of chromosomes (triploidy
or tetraploidy) or the X chromosome or Y chromosome.
Deviations from the normal number
of X or Y chromosomes comprise about half of
all chromosomal aberrations in man (total
frequency about 1:400).

Triploidy

Triploidy is one of the most frequent chromosomal
aberrations in man (1). Possible causes
include a diploid spermatocyte, a diploid oocyte,
or fertilization of an egg cell by two spermatozoa
(dispermy, p. 196). Triploidy usually
leads to spontaneous miscarriage within the
first four months of pregnancy. The fetus shows
numerous severe malformations (2), such as
cardiac defects, cleft lip and palate, skeletal defects,
and others. The additional chromosome
setmay be of either maternal or paternal origin,
with different clinical consequences.

Monosomy X (Turner syndrome)

Monosomy X (karyotype 45,XO) is a frequent
chromosomal aberration, representing about
5% of those in humans at conception. However,
of 40 zygotes with monosomy X, only one will
develop to birth. The phenotypic spectrum is
very wide. During the fetal stage, (1) lymphedema
of the head and neck result in cystic hygroma,
large multilocular thin-walled lymphatic
cysts. Congenital cardiovascular defects,
especially involving the aorta, and kidney malformations
are frequent. An important component
of the disease is the absence of ovaries,
which develop only as connective tissue (streak
gonads). Small stature is always a feature (average
adult height about 150 cm). In newborns,
webbing of the neck (pterygium colli) may be
present as a residual of the lymphedema (clinical
picture of Ullrich–Turner syndrome). On
the other hand, the manifestations may bemild
(2). Very frequently, pure monosomy is not
present, but rather chromosomal mosaicism
with normal cells (45,XO/46,XX) or a structurally
altered X chromosome (deletion of the
short arm, isochromosome of the long or short
arm, ring chromosome, or other).

Additional X or Y chromosomes

An additional X chromosome in males (47,XXY)
leads to the clinical picture of Klinefelter syndrome
after puberty when untreated (1). This
includes tall stature, absent or decreased
development of male secondary sex characteristics,
and infertility due to absent spermatogenesis.
With an additional Y chromosome
(47,XYY) no unusual phenotype results (2). Girls
with three X chromosomes (47,XXX) are also
physically unremarkable (3). However, learning
disorders and delayed speech development
have been observed in some of these children.

Wide spectrum of chromosomal

aberrations in human fetuses
The relative proportions of the various trisomies
observed in fetuses after spontaneous
abortion differ. The most frequent is trisomy 16,
which accounts for about 5% of all autosomal
trisomies. Autosomal monosomies lead to
death of the embryo within the first days or
weeks.

Deletions and Duplications

Deletions and duplications are important structural
aberrations of chromosomes. Deletion,
which causes hemizygosity and functional haploinsufficiency
for the loci involved,may occur
de novo or be the result of the meiotic segregation
of a parental balanced reciprocal translocation
(see p. 198). Duplication of a chromosomal
segment leads to partial trisomy, resulting in
functional imbalance of the genes contained in
the involved region.

Deletion 5p–: Cri-du-chat syndrome

In 1963, Lejeune and his co-workers in Paris described
children with a partial deletion of the
short arm of a chromosome 5 (5p–) and retarded
mental and physical development.
About 15% of the parents show a translocation
of chromosome 5. In these cases, the risk of recurrence
of the disorder is increased. Affected
infants have prolonged, high-pitched crying resembling
that of a kitten (cri-du-chat, cat cry).

Deletion 4p–:Wolf–Hirschhorn syndrome

Described in 1964 independently by U. Wolf in
Freiburg and K. Hirschhorn in New York and
their co-workers, this is a characteristic phenotype
resulting from a partial deletion of chromosomal
material of the short arm of a chromosome
4. Variable but considerable mental and
statomotoric retardation is associated with
characteristic facial features (1, 2) and with
midline defects (cleft palate, hypospadias),
coloboma of the iris, congenital heart defects,
and other malformations. In some patients the
deletion can only be detected by FISH. The
simplified map of 4p16 (3) shows the critical
chromosomal region

Microdeletion syndromes

Of the more than 20 different microdeletion
syndromes (for review see Spinner and
Emanuel, 1996; Budarf and Emanuel, 1997)
three are presented here. The Williams–Beuren
syndrome (1, McKusick 194050, 130160) usually
presents with characteristic facial features
(“elfinlike”), infantile hypercalcemia, supravalvular
aortic stenosis, growth retardation,
and impaired mental development. The underlying
deletion involves the long arm of chromosome
7 at q11.23. The gene for elastin (ELN) is
lost most frequently. Deletion of 22q11 leads to
a group of clinically different but overlapping
disorders (DiGeorge syndrome, McKusick
188400), characterized by absence or hypoplasia
of the thymus and the parathyroid glands
and malformations of the aortic arch; velocardiofacial
syndrome, McKusick 192430; conotruncal
cardiac defects, McKusick 217095; and
others (2). The Rubinstein–Taybi syndrome
(McKusick 180849) is characterized by typical
facial features (3), broad thumbs and toes, and
their associated radiological changes, mental
retardation, and other features. A deletion of
16p13.3 is detectable in about 12% of patients.
Point mutations in the CREB-binding gene (CBP
gene) cause this disorder.

Phenotype of duplication 5q at different ages

A unique duplication illustrates the similar facial
phenotypes at different ages: in a fetus at 22
weeks gestation (1), in a 5-month-old infant (2),
and in an 8-year-old child. The affected individuals
are siblings in one family. The partial
duplication 5q33-qter resulted from a paternal
reciprocal translation (Passarge et al., 1982). A
number of other duplications are associated
with characteristic phenotypes.