Angelman Syndrome is caused by a severe reduction of expression of the gene UBE3a in the brain. Due to genomic imprinting, only the maternal copy of UBE3A is expressed in the brain. . UBE3A is a ubiquitin ligase whose function and targets relevant to AS are still unknown.
15q11.2-q13 deletions (~68% of cases)
The majority of AS cases are caused by deletions on the maternal copy of Chromosome 15. The deletion thus removes the normal expression of this gene in AS individuals.
UBE3A mutations (~11% of cases)
In these individuals, mutations in the UBE3A gene either prevent its expression or function. Thus these individuals do not have the appropriate levels of functional UBE3A in the brain.
Uniparental disomy (UPD; ~7% of cases)
In UPD, the individual has two copies of paternal Chromosome 15. Because UBE3A is not expressed from the paternal copy, these individuals lack normal levels of UBE3A in the brain.
Imprinting defect (~3% of cases)
These individuals may have a deletion of the imprinting center on Chromosome 15, but cases can also be caused by loss of imprinting information during the mother’s oogenesis. Loss of imprinting will prevent expression of the maternal UBE3A gene in the brain.
In these individuals, all testing for Angelman Syndrome is normal, but they still meet the diagnostic criteria for AS. These individuals may have as yet unrecognized mutations that affect UBE3A or genomic imprinting on Chromosome 15. Please note that there are several other syndromes that present like AS that can be tested for.