Genetic causes of Prader-Willi Syndrome
Genomic imprinting
Each human cell consists of a complete set of chromosomes consisting of 2 sex chromosomes, which determine the sex of a human being, and 22 pairs of chromosomes, each carrying the genetic information of the mother and father. All 46 chromosomes carry our genetic material, i.e. all the information necessary for the structure and function of our body. The formation of germ cells (egg and sperm cells) can lead to spontaneous changes in the genetic material (chromosomal defects and gene mutations).
Some changes are only minor and have no recognisable effects. But others do. For the Prader-Willi Syndrome, a section on the long arm of chromosome 15 is relevant. One of the characteristics is that several genes are produced through the process of genomic imprinting (narrow imprinting), methylated on the maternal chromosome and immobilised, i.e. they are only active on the paternal chromosome. If this paternal information is lost, PWS develops. This can have three different causes:
Deletion
Chromosome 15 is not fully formed at the site where the paternal part of genetic information is located. There is a small piece missing, which means that the appropriate information is also missing. This so-called “deletion” is the most common form of Prader-Willi Syndrome (approx. 70%). Only at high resolution is the absence of a piece of chromosome visible under the microscope. With normal parental chromosomes, the risk of recurrence is not increased. Very few patients have an unusually small deletion: this only affects one gene site (SNORD116).
Uniparental disomy
If a second maternal chromosome 15 is present instead of a paternal chromosome 15, it is referred to as a maternal uniparental disomy (UPD). Similar to deletion, the paternal information in the long arm of chromosome 15 is missing. UPD occurs in 25-30% of people with PWS. With normal parental chromosomes, the risk of recurrence is not increased. Similar to Down’s syndrome, however, the risk of UPD increases with maternal age.
Imprinting error
If the genes relevant for PWS are not only shut down in the maternal chromosome, but also on the paternal chromosome 15, it is referred to as an imprinting error. Although this is a structurally normal paternal chromosome, this situation is similar to UPD. This is the rarest form of Prader-Willi Syndrome; only 1% of people with PWS have an imprinting error. In most cases, the “misprint” of the paternal chromosome 15 is a one-off error and the risk of recurrence is not increased. In less than 10% of these cases, i.e. in less than 0.1% of people with PWS, the imprinting error is the result of a mutation in the imprinting centre of chromosome 15. There may be a 50% risk of recurrence. Since such a mutation only occurs through being inherited from the father and not from the mother, it can skip generations and very distant relatives can have PWS.
Chromosomal defect
Possible appearance of people with PWS
Prader-Willi Syndrome is caused by a spontaneous chromosomal disorder. However, because the syndrome has a genetic cause, it is referred to as a hereditary disease. So far, no direct inheritance of PWS has been observed. This is probably because men with PWS cannot conceive a child. However, women with PWS are not excluded from having a child. If they have PWS due to deletion, they have a 50% risk of having a child with Angelman syndrome. Such cases have been described.
It is thanks to Professor Bernhard Horsthemke of the Institute of Human Genetics at Essen University Hospital that the Prader-Willi Syndrome has been recognised early since 1993.
This has had a decisive influence on the opportunities and development of people with PWS. In the so-called methylation test, a few millilitres of blood from a newborn are sufficient to confirm or rule out the clinical suspicion. At the same time a deletion can be detected or excluded.
In this way, the majority of all people with PWS can be classified. The test also detects a UPD and an imprinting error, but cannot distinguish between these two causes. Additional examinations are necessary to calculate the differentiation and exact probability of the risk of recurrence, whereby blood samples of the parents also have to be examined.
A normal amniocentesis or chorionic villus sampling (removal of chorionic tissue) during pregnancy can only detect PWS if a methylation analysis is also carried out.
The early detection of Prader-Willi Syndrome and the many support options, such as the use of growth hormones from infancy and psychosocial support, have greatly improved the life situation of people with PWS in recent years.
- Small stature/often very small hands and feet.
- Possible facial features: narrow face with small forehead, almond-shaped eyes and a triangular mouth. Children with PWS are often very pretty.
- Sometimes people with PWS have lighter skin and hair than their parents.
- People with PWS have short-sightedness and are prone to squinting.
- Due to their viscous saliva, people with PWS often develop saliva crusts at the corners of the mouth and caries (due to lack of dental care).
- Due to muscle weakness and obesity, they often develop a hunchback with a spinal curvature.
Chromosomal defect
Prader-Willi Syndrome is caused by a spontaneous chromosomal disorder. However, because the syndrome has a genetic cause, it is referred to as a hereditary disease. So far, no direct inheritance of PWS has been observed. This is probably because men with PWS cannot conceive a child. However, women with PWS are not excluded from having a child. If they have PWS due to deletion, they have a 50% risk of having a child with Angelman syndrome. Such cases have been described.
It is thanks to Professor Bernhard Horsthemke of the Institute of Human Genetics at Essen University Hospital that the Prader-Willi Syndrome has been recognised early since 1993.
This has had a decisive influence on the opportunities and development of people with PWS. In the so-called methylation test, a few millilitres of blood from a newborn are sufficient to confirm or rule out the clinical suspicion. At the same time a deletion can be detected or excluded.
In this way, the majority of all people with PWS can be classified. The test also detects a UPD and an imprinting error, but cannot distinguish between these two causes. Additional examinations are necessary to calculate the differentiation and exact probability of the risk of recurrence, whereby blood samples of the parents also have to be examined.
A normal amniocentesis or chorionic villus sampling (removal of chorionic tissue) during pregnancy can only detect PWS if a methylation analysis is also carried out.
The early detection of Prader-Willi Syndrome and the many support options, such as the use of growth hormones from infancy and psychosocial support, have greatly improved the life situation of people with PWS in recent years.
Possible appearance of people with PWS
- Small stature/often very small hands and feet.
- Possible facial features: narrow face with small forehead, almond-shaped eyes and a triangular mouth. Children with PWS are often very pretty.
- Sometimes people with PWS have lighter skin and hair than their parents.
- People with PWS have short-sightedness and are prone to squinting.
- Due to their viscous saliva, people with PWS often develop saliva crusts at the corners of the mouth and caries (due to lack of dental care).
- Due to muscle weakness and obesity, they often develop a hunchback with a spinal curvature.