Inherited Imprinting Disorders
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Mutations causing Angelman Syndrome most frequently result from large de novo deletions of the maternally inherited region of chromosome 15q11-q13 and in rare cases of paternal uniparental disomy (UPD). Either mechanism will result in the loss of maternally expressed genes from this region, thus resulting in AS.
Angelman Syndrome can also be caused by de novo or familial mutations in the ubiquitin protein ligase UBE3A gene, which is located within this critical region of chromosome 15. Thus, the screening for mutations in UBE3A in patients either diagnosed or suspected to have AS is warranted.
Our test will detect deletions and UPD causing AS. It does not include UBE3A mutations. Therefore, we recommend to start with the deletion/UPD test and then, if negative, screen for UBE3A mutations, which is available through other molecular diagnostic laboratories.
The most common type of mutation causing PWS is a deletion in the paternally expressed region of chromosome 15, resulting in the presence of only the maternal region, which is silenced and functionally not expressed, thus culminating in the lack of gene expression from this segment of chromosome 15.
In about 30% of cases of PWS, two copies of chromosome 15 are indeed present, however, they both originate from the mother, a process called maternal uniparental disomy (UPD). Since in this region of chromosome 15, the maternal copies are normally silenced, an individual with maternal UPD will have no functionally expressed paternally genes and will therefore develop PWS.
Our test, which is based on a methylation sensitive Southern blot assay, will detect deletions and UPD causing PWS, but will not differentiate one from the other. Although it is clinically not indicated to determine whether PWS is caused by deletion or UPD, fluorescent in situ hybridization (FISH) of this segment of chromosome 15 may be performed in a Cytogenetics Laboratory to ascertain whether two copies or one copy of chromosome 15 are present. A molecular test positive for PWS and a FISH test showing 2 copies of chromosome 15 indicate that PWS is caused by UPD. On the other hand, a molecular test positive for PWS and a FISH test indicative of one copy of chromosome 15 demonstrate a paternal deletion. Although the Cytogenetics assay will detect deletions causing PWS, it will miss PWS caused by uniparental disomy, thus justifying the use of the molecular test to diagnose PWS caused by either deletion or UPD.