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- Some types of Prader-Willi syndrome (PWS) have more genes affected, causing greater symptom severity.
- Older age of the mother is the only clearly established risk factor of PWS.
- PWS usually doesn’t run in families, but about 3% of people have a type that can be inherited.
Prader-Willi syndrome (PWS) is caused by genetic errors on chromosome 15 that are present from birth.
Which Part of Your Genes Are Affected?
Prader-Willi syndrome results from a problem with DNA. DNA is packaged into 23 protein-containing pairs of chromosomes that carry genes. People with PWS have a problem in a specific region of chromosome 15, region 15q11-q13. When you have PWS, the genes in that region can’t be accessed normally, and certain important proteins can’t be made. This loss of function of the specific genes is what leads to PWS symptoms.
The 3 Main Kinds of Genetic Mutations
Most of the time, you get two copies of every gene, one from each parent. For certain genes, the body normally “turns off” one of the genes.
If a gene is turned off, your body won’t make proteins from it. Some genes are normally turned off in the gene you got from one parent but "turned on" in the gene from the other parent.
A lot of the genes affected in PWS are paternally imprinted, meaning that only the gene you get from your father is turned on and able to be used. That's important for understanding the three main types of mutations.
1. Paternal Chromosome 15 Deletion
The most common cause of PWS is a deletion of the region of chromosome 15 from the father's side. Because of paternal imprinting, that means that the person can’t make many of the genes found in this region, even though the gene from their mother is ok. This kind of genetic problem affects about 60-65% of people with PWS.
Some of these deletions are a little bigger than others. In people with a larger type 1 paternal deletion, a few more genes are affected than in people who have a smaller deletion. That's why the smaller type 2 deletion is often less severe.
People with a type 1 paternal chromosome deletion tend to have more issues with obsessive-compulsive disorders, mental disabilities, and behavioral problems compared to those with type 2 or other types of PWS. That’s because it affects more genes compared to these other types.
2. Maternal Uniparental Disomy
The next most common cause affects about 35% of people with Prader-Willi syndrome. A disomy means that you have two copies of a certain chromosome, the way you should. But with maternal uniparental disomy, someone gets two copies of chromosome 15 from their mother and no copies from their father.
For most of the genes on chromosome 15, this doesn’t cause a problem because they aren’t imprinted. However, many of the genes in this specific region aren’t usually turned on in the mother, so those proteins don’t get produced, resulting in PWS symptoms.
Because of some differences in the genes affected, these individuals tend to have slightly different symptoms than people who have deletions. For example, they are less likely to have PWS facial features or severe seizures. They tend to have fewer behavioral issues, but they are more likely to have autism and psychosis.
3. Imprinting Defect
Roughly 3% of people with PWS have it from an imprinting defect. They have the genes from chromosome 15 from both their mother and their father. However, they have a small error in the part of the chromosome that controls imprinting. The father’s genes in this area don’t get "turned on" properly, resulting in PWS symptoms. Potential symptom differences in this type aren't as well studied.
What Causes the Genetic Mutations?
People with PWS have mutations (alterations) in their genes. The mutations usually happen during the process of making reproductive cells (sperm cells or egg cells).
All your DNA gets copied and recombined in different ways when making reproductive cells. This process, called meiosis, is complicated, so it’s not uncommon for errors to creep in.
Usually, these mistakes, called spontaneous mutations, don’t matter very much. In fact, every human being has roughly 70 new mutations in their DNA that weren’t present in their parents’ DNA.
Sometimes, a mistake is so important that it causes an early miscarriage right after conception. Other times, a mistake leads to a specific genetic error that ultimately causes PWS.
Does Prader-Willi Syndrome Run in Families?
Usually not, but sometimes.
If your child has a parental chromosome deletion (type 1 or 2) or maternal uniparental disomy, the chance of having another child with the condition is less than 1%. Similarly, you wouldn’t have an increased risk of having a child with PWS if your aunt, sibling, or cousin has the condition.
For the minority of people who have an imprinting defect, PWS is hereditary. In these cases, the father has an error in the imprinting region of the genes he received from his mother. He doesn’t have PWS himself since the gene he got from his father works fine, but he has a 50% chance of passing on PWS to a future child.
Genetic testing can reveal which kind of mutation is present.
Risk Factors of Prader-Willi Syndrome
Prader-Willi syndrome happens equally in females and males. It occurs in people of all ethnicities at roughly equal rates.
Scientists have only clearly identified one risk factor of PWS. Women who get pregnant at an older age—about 35—have higher risks of having the maternal uniparental disomy form of PWS. This is similar to other chromosomal disorders like Down syndrome.
