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.


Genetic types of PWS

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:
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.

 

The importance of epigenetics in Prader-Willi syndrome

Each cell of the human body contains genetic material in its nucleus. This genetic material, made up of two strands of DNA linked together as a 'double helix', are arranged into what are referred to as chromosomes - in humans there are 23 pairs of chromosomes, with one in each pair inherited from the father and one from the mother. Men and women have a similar arrangement of chromosomes for 22 of these pairs, but one pair differs (numbered as pair 23), with men having one X and one Y chromosome and women having two X chromosomes but no Y chromosome.

DNA includes approximately 40,000 genes that code for individual proteins, which are the building blocks of the body. Other parts of the DNA that are not coding for genes have important regulatory functions. The sequence of DNA is identical in all cells of any given person but quite normally varies between individuals (except for identical twins) as, in the formation of sperm and ova, there is a process whereby the combination of genes that are passed on at fertilization varies. It is this variation that partly or largely accounts for the difference in physical and other characteristics that make each of us unique.

Major abnormalities of specific genes can lead to specific disorders or illnesses - this is often as a result of a fault or 'mutation' in the gene that can then no longer function normally.

DNA therefore is the fundamental genetic code that is unique to each of us.

The term 'epigenetics' refers to processes that then follow in the decoding of the DNA and which accounts for observed differences, for example, between organs of the body or between individuals where such differences are not as a result of differences in the DNA code of individuals - rather, these differences are due to some other process that has modified the way that genes are 'expressed' and function.

The most obvious example of this is the fact that all organs (heart, liver, brain etc) in an individual person's body contain the same DNA code but the genes that are 'expressed' in the liver as opposed to the brain, for example, are very different - thus leading to the development of a specialist organ able to carry out specific functions. This is an example of 'epigenesis' - the modifying of gene expression by some mechanism other than by altering the underlying DNA code.

 
The expression of the gene or genes (as yet not fully identified) located in the region referred to as q11-13 on chromosome 15 that are implicated in PWS are subject to an unusual and relatively rare 'epigenetic' modification. Normally the two copies or 'alleles' of any given gene (one from mother and one from father) are equally expressed, but for a small proportion of genes this is not so. It is the case with some genes that only the copy inherited from the father or only the copy inherited from the mother is expressed. The other copy is silenced due to being 'imprinted'. In the case of PWS, the suspect genes located on chromosome 15 at q11-13 are like this. It is only the copy or allele that is inherited from the father that is normally expressed. The
maternal copy is quite normally 'imprinted' and not active. Under normal circumstances having just this one active copy from the father is sufficient but when a person has a deletion at q11-13 on the paternal copy of chromosome 15 and the only active copy of the relevant gene or genes are deleted and are lost, PWS ensues.  

Similarly when both copies of chromosome 15 are abnormally inherited from the mother, and the father's chromosome 15 is not present (disomy or UPD), neither copy of the relevant genes are active, as both copies are switched off, as both are inherited from the mother, rather than one from the father and one from the mother.

Although rare (accounting for 1% or 2% of people PWS), a mutation of the imprinting centre on chromosome 15 also results in PWS, further underlining the importance of epigenetics. In these cases there is no loss or physical change in the relevant genes; simply their epigenetic control has been disrupted, resulting in no expression from the copy inherited from the father. 

It is becoming increasingly apparent that these unusual genes, whereby the gender of the parent of origin can effect whether they are expressed or not, are very important in human development, and there are complex theories put forward as to why such genes have developed during evolution. In the case of PWS it is clear that the relevant genes must be epigenetically modified in the way described above. In addition, the observation that certain forms of mental illness are more common in those with the UPD form of PWS, compared to those with PWS due to a deletion, suggests that there are other genes on chromosome 15 that have the opposite 'imprint' to that observed in PWS - only the copy of this presumed, but unidentified gene, that is inherited from the mother is expressed and the copy from the father is switched off. These other genes are not directly relevant to the core features of PWS, but they may be important in understanding the reasons for this excess of specific mental illnesses in those with UPD.

As knowledge about imprinted genes increases, and what they do and where in the body they are most actively expressed is established, then it is likely to become possible to understand what goes wrong when these crucial genes are not working. This is where studies using mice whose genes have been modified to be like that which occurs in PWS become very important, as such 'mouse models' provide the means for investigating the brain abnormalities that might explain the over-eating behaviour etc.


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.

 

© PWSA UK

Thank you 

We are most grateful to the M&G Staff Charity Fund for their support for the revision and production of this document. 

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