Prader-Willi syndrome (PWS) is caused by specific genetic changes affecting gene expression on a particular region of chromosome 15. Essentially, certain genes on chromosome 15 that are supposed to be active are not, due to a variety of genetic mechanisms.
Here's a breakdown of the different genetic mechanisms that can lead to PWS:
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Paternal Deletion (Approximately 70-75% of cases): The most common cause is the deletion of a specific region on the paternally inherited chromosome 15. This means that a portion of the chromosome contributed by the father is missing.
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Maternal Uniparental Disomy (UPD) (Approximately 20-25% of cases): In this instance, a person inherits two copies of chromosome 15 from their mother and no copy from their father. Because certain genes in the PWS region are only active on the paternal chromosome, having two maternal copies results in those genes being inactive.
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Imprinting Defect (Approximately 1-3% of cases): Imprinting is a process where certain genes are expressed (turned on) or silenced (turned off) depending on which parent they are inherited from. An imprinting defect means that the paternal chromosome 15 has the wrong imprinting pattern. Even though the genes are present, they are incorrectly silenced as if they were from the mother. This can involve an issue with the imprinting center on chromosome 15.
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Rare Genetic Rearrangements (Very rare): Occasionally, PWS can be caused by a translocation or other structural change on chromosome 15 that disrupts the normal function of genes in the PWS region.
In all of these situations, the critical feature is the lack of active copies of specific genes in the PWS region of chromosome 15 that are normally expressed only from the paternally inherited chromosome. These genes play a vital role in regulating various functions, including appetite, metabolism, growth, and behavior. The absence of these active genes leads to the characteristic features of Prader-Willi syndrome.
