The Genetics of PWS

PWS is a complex genetic syndrome and research is uncovering many variations within it. This 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 form one of 4 different genetic abnormalities. These are:
Either:  1. A small deletion on chromosome 15.
Or:   2. Chromosome 15 maternal disomy.
Or:   3. A translocation of chromosomes involving chromosome 15.
Or:   4. 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. A translocation is an exchange of material between or within chromosomes, and can involve any chromosome, not just 15. When the translocation is “balanced” 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 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 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 heterogenous characteristics.

If you are a parent, and 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 is also part of the initial diagnosis procedure in PWS. A sample is taken from the child in the first instance. Chromosomes and DNA are both obtained from the white cells. If the child has a chromosome deletion new techniques such as Fluorescent In Situ Hybridization (FISH) may be used to identify this. Sometimes it is necessary to check parental blood samples as well.  If a chromosome translocation is found  then testing of the wider family may be indicated.

Glossary
Chromosome Each cell in the body normally carries 46 chromosomes, numbered in pairs from 1 to 23. One chromosome of the pair is normally inherited from a person's mother, and the other from their father. Chromosomes contain genes: the hereditary factors which determine our body make-up.
Cytogenetics The science concerned with the study of normal and abnormal chromosomes, and of their behaviour. Cytogenetics is developing increasingly sophisticated techniques for studying the make-up of chromosomes on very microscopic levels.
De novo New. Never occurred before within a family.
Deletion A small piece of material which is missing from a chromosome.
Disomy Both chromosomes of a pair inherited from one parent, rather than (as is normal) one coming from the mother and one from the father.
Familial A disease or condition which affects several members of one family.
Heterogenous Different in appearance or make-up.
Imprinted Marked so that there are differences between maternal and paternal inheritance.
Maternal Coming from the mother.
Non-deletion All chromosomes are normal in their make-up, with no pieces missing.
Paternal Coming from the father.
Recurrence risk Likelihood of a disease or condition occurring again in any given family.
Siblings Brothers and/or sisters.