What are chromosomes?
Chromosomes are the structures in which our hereditary material (DNA) is packed.
A healthy person has 46 chromosomes (23 pairs). One chromosome of each pair (i.e.
a total of 23 chromosomes) is donated by each parent to the fetus. Twenty-two pairs
are called autosomes and the other pair are the sex chromosomes (X and Y). Females
have two X chromosomes and males have one X and one Y. The chromosome pairs are
arranged and numbered by size and shape, and each has different genes. Because there
are two copies of each chromosome, there is effectively a duplicate gene system
(one maternal and the other paternal), each identical in sequence to the other.
Disorders in the number and structure of the chromosomes may cause defects, genetic
syndromes and/or developmental retardation. Almost any insertion or deletion of
chromosomal material (mainly from autosomes) may manifest in mental retardation. The best known defect is
an extra chromosome 21, so that there are three copies instead of two, and this
causes Down syndrome.
Chromosome analysis (karyotype)
An examination of all the chromosomes can be carried out on blood cells and also
in a prenatal test (amniocentesis,
villus sampling, cordocentesis).
In this examination, the number of chromosomes and the structure of each are analyzed.
Chromosome disorders (general terminology)
Trisomy - a condition in
which there is an extra chromosome, with three of the same type being present rather
than two. For example: trisomy 21 (
Down syndrome ), trisomy 18,
Monosomy - a condition in
which an entire chromosome is missing, with only one being present rather than two.
For example: monosomy X ( absence of an X chromosome, Turner syndrome ).
Translocation - the exchange of chromosomal material between two chromosomes
of different pairs. A translocation is said to be balanced when a change occurs
in the location of certain genes, but there is no gain or loss of genetic material.
If a person carries a balanced translocation, with no change in the amount of genetic
material and no damage to the genes has occurred, he will be healthy, but is at
increased risk of having a child with an unbalanced chromosome arrangement. In such
a child, the chromosome arrangement will include gains or losses of genetic material
that result from the parental translocation. Some fetuses that have an unbalanced
chromosome arrangement abort spontaneously at the beginning of pregnancy, so that
some of the couples where one partner carries a balanced translocation have recurrent
miscarriages. It is important to note that a parent carrying a balanced translocation
can also have healthy children without a translocation or children carrying a balanced
translocation like that of the parent. In these cases, where the chromosome arrangement
is identical to that of the affected parent, there are no clinical manifestations.
This can be diagnosed during pregnancy by amniocentesis or chorionic villus sampling.
When a balanced translocation is diagnosed in a fetus in a prenatal test, and when
the chromosome arrangement in each of the parents is normal (without a translocation),
this is described as a "de novo" translocation. In these cases there is an increased
empirical risk of defects and mental retardation in the fetus. The risk is approximately
7% higher than the standard risk in the general population, which is approximately
2% - 3%. The exact risk varies according to the type of translocation and the results
of other tests such as an ultrasound scan.
There are two types of translocations: Robertsonian and reciprocal.
translocation - this is a condition in which there is almost complete fusion
between two chromosomes. This type of translocation is only possible with chromosomes
13, 14, 15, 21 and 22 because of their shape - they have only long arms and no short
arms. If a translocation of this type is identified in the fetus and in a balanced
form in one of the parents, the child will be healthy in about 98% of cases, but
nevertheless it is important to check for conditions that may be associated with
anomalies in the fetus, even though the translocation in the fetus is apparently
balanced. The main condition to look for is uni-parental disomy (UPD). Here the
fetus receives two chromosomes of the same pair from a single parent, instead of
the normal situation in which it receives one of each pair from each parent. This
phenomenon can be diagnosed using molecular genetics involving testing at the DNA
rather than the chromosome level.
translocation - this is a condition in which there is an exchange of chromosomal
material between two chromosomes of different pairs. Breaks occur in the arms of
each of the chromosomes concerned, and the broken-off part of one chromosome attaches
itself to the other chromosome and vice versa. When the break occurs between the
genes and the genes are not damaged, there are no clinical consequences. However,
when as a result of such a translocation, damage is caused to an essential gene,
a mutation that can cause impaired functioning may arise. This means that a de novo
translocation carries a risk for defects and mental retardation that is about 7%
higher than the regular risk. On the other hand, if one of the parents is found
to have a break at the same location and he or she is healthy, this proves that
no damage associated with a disease has occurred at the translocation site.
Inversion - in this condition there is
inversion of a segment of one of the chromosomes that results in neither
gain nor loss of genetic material. This means that a person carrying an inversion
is almost always healthy. There is a relatively small risk, however, of having a
child with an unbalanced chromosome arrangement where there may be gains or losses
of DNA. A significant number of such pregnancies abort spontaneously at the beginning
of the pregnancy. An inversion can be detected during pregnancy by amniocentesis
or chorionic villus sampling. There are a number of very common inversions in the
population, especially in chromosomes 2, 9 and 17, which in most cases are transmitted
unchanged from parent to child. In these cases there is usually no reason to examine
the fetus, because the likelihood that there will be a problem in the fetus is very
Mosaicism - in this condition a change occurs in the structure or shape
of the chromosome or in the chromosome arrangement usually after the fetus is formed.
Here the fetus starts developing in the uterus with a normal chromosome arrangement,
but when it reaches the stage of multiple cells, one cell might develop a chromosome
anomaly. From then on, all the cells that are derived from this one cell will also
contain the same abnormal chromosome arrangement. This means that in certain body
organs the person has a combination of cells, some with a normal genetic structure
and others with an abnormal genetic structure. This situation is known as mosaicism. The clinical significance of mosaicism depends
on the number of abnormal cells and their function, i.e. what they are responsible
for. In most cases a chromosome disorder resulting from mosaicism is milder than
one that occurs when all the cells have the same abnormal chromosome arrangement.
Because mosaicism is present in only some of the body organs, tissues and cells,
there is a possibility that it will not be diagnosed in chromosome tests performed
on blood or amniotic fluid.
Microdeletions of chromosomes
- there are a number of syndromes that are caused by microdeletions (deletions that
are so small they are barely, if at all, detectable microscopically) in chromosomes,
e.g. Williams syndrome,
which is caused by a deletion of a small segment of chromosome 7; VCF syndrome,
caused by a deletion of a small segment of chromosome 22; cat cry (cri du chat)
syndrome, caused by a small deletion of chromosome 5, and many others. A very small
number of these deletions can be identified using classic cytogenetic diagnostic
methods, but most can be diagnosed only after birth and only after clinical suspicion
of their existence has been established. Diagnosis is made by carrying out fluorescent
staining (FISH - fluorescent in-situ hybridization) or by molecular methods.
Deletions in chromosome
Y - in cases where there is a deletion of part of the short arm of
chromosome Y, a female phenotype is found because of the deletion of a gene called
SRY that is responsible for testicular development. This condition is rare. Deletions
in the long arm of chromosome Y that do not cause a loss of the normal male phenotype
but that may be associated with the absence of sperm formation are more common.
In most of these cases the deletion is in a region that does not encode genes and
thus has no clinical significance. If a short Y chromosome is identified, the father
should be examined. When the father's Y chromosome is identical to that found in
the fetus, the deletion has no significance, but when the father does not have an
identical Y chromosome structure, and paternity is not in doubt, the deletion in
the fetus may have consequences for the offspring's final height and sterility (because
of a lack of sperm cells), although these conditions can be treated.
Some men who are sterile have deletions in certain regions of the long arm of the
Y chromosome. These can be detected using molecular methods.
Examples of common numerical disorders in the autosomes (the non-sex-determining
Down syndrome, trisomy 18 trisomy
Numerical disorders of the sex chromosomes (X and Y)
Disorders in the number of sex chromosomes (trisomies and monosomies) differ from
similar problems in the autosomes. Whereas disorders in the number of autosomes
entail such significant defects as mental retardation etc., in sex chromosome disorders
the problems are less severe in comparison but of greater scope. Sometimes the level
of intelligence is almost normal, but there can be severe problems of fertility,
stature and mental development. When a couple seeks genetic counseling because one of these conditions
has been detected in the fetus, they often face severe dilemmas.
Examples of numerical disorders in sex chromosomes: Turner syndrome (XO), Klinefelter syndrome (XXY), XXX (triple X) syndrome and XYY syndrome.
The risk for recurrence of chromosome disorders
In order to evaluate the risk for the recurrence of a chromosome disorder, it is
important to know what disorder the first fetus had. It is important to note that
even when the risk of recurrence is not significantly high relative to that in the
general population (which is about 1:300), it is advisable that every couple with
a history of a chromosome disorder in pregnancy should undergo prenatal testing
for fetal chromosome analysis in every future pregnancy.
- In cases of numerical chromosome disorders (trisomy or monosomy), the risk of recurrence
is 1% higher than that of other women of the same age. The risk is slightly less
when the fetus has a numerical disorder involving the sex chromosomes. The maternal age is also a factor that affects the incidence
of numerical chromosome disorders.
- When one of the partners has a numerical disorder in one of the sex chromosomes,
there is a theoretically increased risk of having an infant with a similar sex chromosome
disorder. In reality, however, this is usually not the case unless intra-cytoplasmic
sperm injection (ICSI) is performed.
- When the chromosome disorder in a previous pregnancy was structural (e.g. translocation,
inversion, minimal deletions or insertions) and the chromosomal structure of both
parents is normal, the risk of recurrence is not significantly higher than that
in the general population. However, the risk is not zero, because it can happen
that the chromosomal structure of a parent looks apparently normal, but there is
an abnormality in the parent's gametes (mosaicism). This can be transmitted to the
fetus. However, as noted, this condition is rare, and the empirical risk is not
significantly greater than that in the general population.
- When the chromosome disorder is structural and has been demonstrated in one of the
parents in a balanced or unbalanced form (translocation, inversion, marker chromosome,
etc.), there is a significant risk for recurrence in future pregnancies. The empirical
risk depends on two parameters: the chromosomes involved and whether the problem
is in the husband or wife.
- When the chromosome disorder in the fetus is of mosaic type and the parents have
normal chromosomes, the risk of recurrence is not significantly increased because
the disorder is not in the sperm or ovum that made the fetus and therefore is not
present in the parents' chromosomes, but rather occurred in the fetus after fertilization.
Chromosome to DNA