Diagnostic Testing Approach in Angelman Syndrome

Diagnotic testing for AS Diagram

Testing for AS is summarized in the diagram. The most efficient method to begin the diagnostic study is the methylation test. This test costs about $300 and screens for three of the four known genetic mechanisms that cause AS and thus diagnoses about 80 to 85% of individuals with AS. If it is abnormal, one of three genetic mechanisms, as indicated in the diagram, is going to be the cause of AS. A FISH (fluorescent in situ hybridization) 15 test or comparative genomic hybridization (CGH) test (both use blood testing) is then the next test to be performed. If either or both prove to be negative, further study is needed to determine whether the genetic causation, given the abnormal methylation test, is either paternal uniparental disomy or an Imprinting Center defect.

Often the first test to be obtained is either a FISH 15 or a comparative genomic hybridization (CGH) test, the latter test is a new type of molecular chromosome study. The FISH 15 and CGH tests will only detect the chromosome deletion problem. It is important to remember that if one of these were the first tests performed, and the result was negative, there are still other genetic mechanisms that could cause AS so additional diagnostic testing is needed.

If the DNA methylation test is normal, the next logical test would be DNA sequencing of the UBE3A gene. About 10% of individuals with Angelman syndrome will have UBE3A mutations, and the current DNA sequencing tests are generally very good in identifying causative mutations. However, many individuals in whom the UBE3A gene sequencing test is performed turn out to have a normal test result and thus they do not have any of the four genetic mechanisms (assuming they also had a normal methylation study) that cause AS. In these situations, it is still possible that the individual could have AS but other genetic mechanisms that lead to AS in these situations have not yet been identified. The most likely scenario in these cases is that they have a condition that mimics AS. For these individuals, renewed clinical scrutiny and more advanced genetic testing often occurs, such as obtaining comparative genomic hybridization studies to ensure that there is no small deletion or duplication located somewhere else in the genome.

Reviewed 10-8-2015
Charles Williams, MD