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THE GENETICS OF
PRADER-WILLI SYNDROME
by Tessa Webb, Clinical Genetics Unit, Birmingham Maternity Hospital and
Jackie Waters, Information Officer PWSA (UK)
This page gives you more information about the genetic background to
Prader-Willi Syndrome (PWS), and the likelihood of you or any other members of
your family having another child with PWS. The information reflects current
knowledge, and therefore may change over time, as more research is carried out.
In the vast majority of cases, the risk of having another child with PWS is
very slight indeed. For example, a study in Australia of 144 families with a
child with PWS found no recurrence. There were 266 living siblings of the PWS
children, and they were all normal.
Current research has shown that the set of symptoms known as Prader-Willi
Syndrome result mainly from one of 4 different genetic abnormalities. These
are:
- A small deletion on chromosome 15.
- Chromosome 15 maternal disomy.
- A translocation of chromosomes involving chromosome 15.
- An error in the imprinting of Chromosome 15.
1: A small deletion on chromosome 15
Approximately, 60-70% of PWS cases are due to a de novo (or new) deletion on
the chromosome 15 inherited from the father. There has been no known recurrence
in any of these families. Theories have been put forward that this is due to
accidental damage to the sperm or the egg at the time of conception, but none
of these have yet been proved conclusively.
2: Maternal disomy
In about 25-30% of cases, Prader-Willi Syndrome can be the result of
maternal disomy (two copies of chromosome 15 coming from the mother instead of
one copy from each parent). These are included in the "non-deletion"
cases. Once again there has not been a known recurrence of maternal disomy in
any PWS family. However, the recurrence risk here is usually given as 0.4% for
two reasons. Firstly, because some non-deletion PWS may be due to something
other than disomy, and secondly because the risk of disomy increases a little
with maternal age. Like the deletion cases, disomy is an accidental occurrence
which occurs at meiosis (the process of cell division which takes place at the
time of conception).
3: A translocation of chromosomes involving chromosome 15
The very few families (less than 5%) which do have a high risk of having
more than one child with PWS are those which carry a translocation involving
chromosome 15. When the translocation is "balanced" (THIS NEEDS
EXPLAINING) then it can pass from one generation to another with no harmful
effect, but it is sometimes possible for it to be passed on in an
"unbalanced" form, and a deletion can result. When a deletion is the
result of a translocation or structural rearrangement involving chromosome 15,
then the recurrence risk can be high. The actual risk in individual families
depends upon the rearrangement which they carry. Fortunately however,
cytogenetic studies can identify these families so that they can receive
appropriate advice.
4. An error in the imprinting of chromosome 15
Chromosome 15 is almost unique in that it carries an imprinted region. This
means that it is marked so that the copy (or homologue) inherited from the
mother behaves differently from the one which comes from the father. Imprinting
explains why the deletions which occur in Prader- Willi syndrome always arise
in the paternal copy of chromosome 15 and why disomy always comes from the
mother. Very occasionally an error occurs in the the setting of the imprint and
Prader-Willi syndrome can result.
Research is continuing into whether there are any differences in development
between those who have a deletion and those who do not. At the present time
there appears to be little difference, except that those who have a deletion
have the more typical PWS facial appearance, with lighter hair than the rest of
their family and light blue/grey eyes. Those without the deletion show more
heterogeneous characteristics.
Dr Tessa Webb of the Department of Clinical Genetics at Birmingham Maternity
Hospital has personally studied over 60 families in the UK. Only one of these
families has had more than one person with PWS, and this family had a 15:22
translocation which was passed on from one generation to another.
If you are in any doubt about whether to have more children, or whether the
condition will be passed on through your other children, ask your paediatrician
or medical specialist to refer you to a genetic counselling centre, where blood
tests can be carried out on you and your child to determine how the chromosomes
have been affected, and if there are any risks in having more children.
Usually, you can arrange for samples of your blood to be taken at your local GP
practice or hospital.
Taking blood samples can also aid initial diagnosis of PWS. Chromosomes and
DNA are both obtained from white blood cells. It is necessary to have blood
samples from both parents as well as the child with PWS for several reasons.
- Firstly, if there is a translocation passing through the family,
then it is necessary to identify which parent is carrying it so that other
members of their family can be checked and given the appropriate information.
- Secondly, the area of the deletion seen in PWS can vary in size
quite considerably, so in order to be sure that a deletion is really there,
comparisons need to be made with the same area on the parental chromosomes.
- Thirdly, to demonstrate that the molecular band pattern in the PWS
region comes only from the mother, with no contribution from the father, as
happens in maternal disomy and in deletions involving the paternal chromosome
15, then the band patterns from both parents must be available for comparison.
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