About Angelman Syndrome
Testing & Diagnosis
These days, there isn’t one definitive test for AS, but rather—and this is good news!—numerous tests. If you are trying to understand the test results of your child or someone else, it is important to know exactly which test(s) the child has had. It is common for parents to know their child was tested for AS and to remember the geneticist telling them the test was either positive or negative, but different genetic errors can cause AS—which means different tests are needed to detect them.
Additionally, about one in ten individuals who have all the key symptoms of Angelman syndrome have normal or “negative” results on all these tests. These individuals may receive a “clinical” diagnosis of AS. This means the individual meets the diagnostic criteria of AS but we don’t know what kind of genetic error is causing their symptoms.
In the early 1990s, the first tests were developed to test Chromosome 15 for deletions. But scientific progress can sometimes inadvertently lead to confusion, as people understandably assume—especially when it comes to genetics—that there is a straight path to a clear and conclusive answer.
Further research into the genetics of Angelman syndrome is likely to yield more causes of AS and, therefore, more tests to confirm the clinical diagnosis. For now, the ones available are:
Standard Chromosome Analysis or Cytogenetics Analysis: Any expectant parent who had chorionic villus sampling (CVS) or amniocentesis during a pregnancy has had a version of this test. This is not a detailed test and only rarely reveals small chromosome errors like the common AS deletions. For more about this test, see here.
The DNA Methylation Test: This test will positively identify about 80% of individuals with Angelman syndrome. Methylation refers to a chemical “tag” added to DNA and can be used to identify whether the DNA was contributed by the mother or the father. For more about this test, see here.
The FISH Test: This test determines if part of Chromosome 15 is physically missing from the individual. But because this test cannot tell us which parent’s chromosome is missing pages, it needs to be performed along with the DNA methylation test to confirm the individual has Angelman syndrome and not Prader-Willi syndrome, a disorder caused by missing a “chapter” from the father’s chromosome rather than the mother’s. For more about this test, see here.
PCR Assay: If an individual has a positive methylation test for Angelman syndrome, but a negative FISH test, then they either have UPD or ICD. A PCR (polymerase chain reaction) test is then used to determine if the individual has two copies of the father’s chromosome 15 (UPD), or one chromosome from each parent but with incorrect methylation (ICD). For more about this test, see here.
UBE3A Sequencing: About 20% of people who have all the symptoms of Angelman syndrome will get negative results on all of the tests listed so far. The next test is to sequence their UBE3A gene directly. Sequencing is like opening up the Chromosome 15 inherited from the mother and looking at the UBE3A “chapter” and carefully spell-checking each word—which is even more complicated than it sounds. For more about this test, see here.
There is greater detail about these tests here.
If you need help understanding or planning your own tests, write to us at community@cureangelman.org.