Prader-Willi syndrome

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Prader-Willi syndrome is a genetic disorder in which up to seven genes on chromosome 15 are missing or unexpressed (chromosome 15q partial deletion). It was identified in 1956 by Andrea Prader, Heinrich Willi, Alexis Labhart, and Guido Fanconi of Switzerland.

Diagnosis/testing

The mainstay of diagnosis is genetic testing, specifically DNA-based methylation testing to detect the absence of the paternally contributed Prader-Willi syndrome/Angelman syndrome (PWS/AS) region on chromosome 15q11.2-q13. Such testing detects over 99% of patients. Methylation-specific testing is important to confirm the diagnosis of PWS in all individuals, but especially those who are too young to manifest sufficient features to make the diagnosis on clinical grounds or in those individuals who have atypical findings.

Fluorescent in situ hybridization (FISH) can confirm prenatal diagnosis when a deletion in the 15q region is suspected after chorionic villus sampling or amniocentesis.

Genetics

PWS is caused by absence of the paternally derived PWS/AS region of chromosome 15 by one of several genetic mechanisms, including uniparental disomy, imprinting mutations, chromosome translocations, and gene deletions. The genes responsible for Prader-Willi syndrome are expressed only on the paternal chromosome. (Interestingly, a deletion on the maternal chromosome causes Angelman syndrome.) This is the first known instance of imprinting in humans.

The risk to the sibling of an affected child of having PWS depends upon the genetic mechanism which caused the disorder. The risk to siblings is <1% if the affected child has a gene deletion or uniparental disomy, up to 50% if the affected child has a mutation of the imprinting control center, and up to 25% if a parental chromosomal translocation is present. Prenatal testing is possible for any of the known genetic mechanisms.