Testing & Diagnosis

Individuals living with AS who have a deletion, UPD, or ICD–which is about 80% of individuals living with AS– all have a specific pattern on DNA methylation testing that confirms the diagnosis of Angelman syndrome. 

This test method can check the DNA methylation AND look for deletions at the same time.  Consequently, it can confirm the diagnosis of AS for individuals who have typical AS deletions, UPD, ICD deletions, and ICD methylation, and it can provide the genotype for typical AS deletions and the ICD deletion genotypes.

About 10% of individuals living with Angelman syndrome have a variant in the sequence of the UBE3A gene, also called a mutation. Sequencing is when the laboratory reads all of the chemicals of the gene, checking to ensure that all are present and in the correct order.  If a variant is found that makes the UBE3A protein nonfunctional or less functional, the individual is said to have Mutation AS.  

CMA is a very common test, designed  to identify missing or extra pieces of DNA.  There are different versions of CMA, which each have different capabilities.  All CMAs can identify the typical AS deletion and provide information about the size of the deletion.  CMA cannot determine whether the deletion is on the maternal or the paternal chromosome, so methylation studies may be needed.  SNP-CMAs can also identify UPD from isodisomy.   

This test uses glowing tags that attach to specific sites on a chromosome to determine if a section of chromosome is missing (deleted) or present.  FISH cannot determine the size of the deletion or whether the deletion is on the maternal or paternal chromosome.  FISH was commonly used in the USA 10-20 years ago, but now most genetics specialists recommend CMA or MLPA so that the size of the deletion can be determined.  

This test is typically performed when an individual has methylation testing consistent with AS but does not have a 15q11.2-13 deletion or UPD.  ICD deletion testing may also be included as part of MS-MLPA.   

This test compares markers found on chromosome 15 between the individual living with AS and that person’s parents to determine if the individual inherited both chromosome 15s from the sperm. This testing requires samples from both parents and may also be called microsatellite analysis or short tandem repeat analysis.  It can detect heterodisomy, isodisomy, and most segmental UPD (where only a portion of the chromosome comes from one parent).      

This test looks at the chromosomes in a small number of cells under the microscope.  It is meant to identify whole extra or missing chromosomes or large extra or missing pieces of chromosomes. Because the deletion that commonly causes AS is not visible under the microscope, standard chromosome analysis cannot be used to diagnose AS; the vast majority of people with AS will have a normal standard chromosome analysis.  Chromosome analysis can be performed to look for chromosome rearrangements, such as two chromosomes stuck together; rearrangements involving chromosome 15 can increase the chance for AS in a person’s children.  

These tests evaluate most of the 20,000 genes all at once.  WES and WGS are typically performed when the diagnosis is unclear or unknown or the healthcare provider is considering many similar conditions.   

WES only sequences the exons, the parts of genes that code for protein, while WGS also evaluates the chemicals in between genes, including sections of DNA important in controlling turning genes on and off. The methods of performing and analyzing WES/WGS vary from laboratory to laboratory. Some labs’ WES/WGS may identify deletions like we see in the deletion genotype and some may not.  If parental samples are provided, some labs’ WES/WGS may identify UPD.  WES/WGS should be able to detect UBE3A mutations. However, because so many genes are evaluated at once, sometimes UBE3A is not completely analyzed. If your loved one had WES/WGS, your genetics team should be able to consult with the laboratory to determine which AS genotypes were ruled out by the testing.