right PWS is related to an epigenetic phenomenon known as imprinting. Normally, a fetus inherits an imprinted maternal copy of PW genes and a functional paternal copy of PW genes. Due to imprinting, the maternally inherited copies of these genes are virtually silent, and the fetus therefore relies on the expression of the paternal copies of the genes. In PWS, however, there is mutation/deletion of the paternal copies of PW genes, leaving the fetus with no functioning PW genes. The PW genes are the SNRPN and NDN genes, along with clusters of snoRNAs: SNORD64, SNORD107, SNORD108 and two copies of SNORD109, 29 copies of SNORD116 (HBII-85) and 48 copies of SNORD115 (HBII-52). These genes are located on chromosome 15 located in the region 15q11-13. This so-called PWS/AS region in the paternal chromosome 15 may be lost by one of several genetic mechanisms, which in the majority of instances occurs through chance mutation. Other, less common mechanisms include uniparental disomy, sporadic mutations, chromosome translocations, and gene deletions. Region 15q11-13 is implicated in both PWS and Angelman syndrome (AS). While PWS results from the loss of PW genes within this region on the paternal chromosome, loss of a different gene (UBE3A) within the same region on the maternal chromosome causes AS. PWS and AS represent the first reported instances of disorders related to 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 region, and up to 25% if a parental chromosomal translocation is present. Prenatal testing is possible for any of the known genetic mechanisms. A microdeletion in one family of the snoRNA HBII-52 has excluded it from playing a major role in the disease. Studies of human and mouse model systems have shown deletion of the 29 copies of the C/D box snoRNA SNORD116 (HBII-85) to be the primary cause of PWS.
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