Genetics of Angelman Syndrome
Normal 15 Chromosome
Humans have two number 15 chromosomes. One is inherited from our mother (M.) and one is inherited from our father (P, paternal). The Angelman syndrome gene (UBE3A) is located at chromosome 15, band q12 (see the image). In the brain, the Angelman gene is primarily expressed from the maternally inherited chromosome 15. The diagrams below illustrate the four known genetic mechanisms that cause Angelman syndrome.
Chromosome Deletion – 68%
This is a large chromosome deletion that removes region 15q12 and its surrounding area from the maternally derived chromosome. It is the most common mechanism and occurs in 68% of all individuals with the syndrome. Because the UBE3A gene has been removed, there is deficient expression of it in the brain; Angelman syndrome results.
This deletion can be screened for by the DNA methylation test, typically performed on a blood sample. Confirmation of the deletion however requires the fluorescence in situ hybridization (FISH) test or a molecular chromosome study (e.g., comparative genomic hybridization test, CGH).
UBE3A Mutation – 11%
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.
Paternal Uniparental Disomy (UPD) – 3%
In this case, Angelman syndrome is caused by the presence of two, normal paternally derived number 15 chromosomes. Since the maternally derived chromosome is absent (and it is the one that expresses the Angelman gene in the brain) Angelman syndrome occurs.
This abnormality can also be screened for the DNA methylation test. Confirmation of UPD however requires further genetic molecular study. Use of polymorphic DNA markers for chromosome 15 is used to identify whether both chromosomes are of paternal origin.
Imprinting Center Defect – 6%
The imprinting center is a small stretch of DNA located in the q12 region that controls whether the Angelman gene is turned on or off. Abnormalities in the imprinting center on the maternally derived chromosome 15 can cause Angelman syndrome in a small percentage of cases.
Imprinting defects can also be screened for by the DNA methylation test. The diagnosis of an imprinting center defect is presumed when the DNA methylation test is abnormal but there is no evidence of chromosome deletion or uniparental disomy. Molecular genetics study is needed to further evaluate the imprinting defect and this testing in only available in a few laboratories. Some individuals with an imprinting defect will have a small DNA deletion within the imprinting center.