In people with Angelman Syndrome, the UBE3A gene from their mother (also referred to as the maternal copy) is impaired in some way, which affects the production of the UBE3A protein needed for brain function. The UBE3A gene is located on Chromosome 15. Normally, we have two copies of the UBE3A gene – one from mum and one from dad. Only the mum's copy works in the brain. In people living with Angelman Syndrome, the mum's copy of the gene is impacted (this alteration is referred to as the genotype ie: Deletion, mutation etc), meaning their brain cells can’t make the protein. This lack of protein affects basic abilities like walking, talking, and other everyday tasks.
In most cases, Angelman syndrome isn’t inherited – particularly those caused by a deletion or UPD. Instead, these genetic changes occur as random events during the formation of reproductive cells or in early embryonic development.
- 15q11.2-q13 deletions (~68% of cases) ~ The majority of AS cases are caused by deletions on the maternal copy of Chromosome 15. Due to genomic imprinting, only the maternal copy of UBE3A is expressed in the brain. The deletion thus removes the normal expression of this gene in individuals with AS.
- 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 centre on Chromosome 15, but cases can also be cause by loss of imprinting information during the mother’s oogenesis. Loss of imprinting will prevent expression of the maternal UBE3A gene in the brain.
- Clinical/Other (~11%) ~ 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 unrecognised 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.
Testing & Diagnosis
Genetic testing for Angelman syndrome can be complicated! Angelman syndrome is always caused by a lack of functional UBE3A protein in the brain. But because there are different genetic causes, also called genotypes (listed above), there are multiple different methods to test for AS. Visit the testing link in the side panel for a quick summary of the typical testing methods currently used in Australia, as well as those historically used. Please note that the available tests for AS have changed over time as our understanding of AS and genetic testing methods has improved.
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