Testing & Diagnosis for Angelman syndrome
Angelman syndrome is typically diagnosed through genetic testing. Because several different types of genetic changes can cause Angelman syndrome, more than one type of test is often needed to confirm the diagnosis and identify the genotype.
What genetic testing can tell you
Genetic testing can do more than confirm a diagnosis. It can also provide information about the underlying genotype, recurrence risk, and eligibility for some clinical trials.
Confirm the diagnosis
Testing can confirm whether the genetic changes associated with Angelman syndrome are present.
Identify the genotype
Knowing the genotype can help explain the underlying genetic cause of AS. Each genotype has characteristics that are more common. Knowing the genotype can provide some information about what to expect in the future.
Clarify chances for family
Different genotypes are associated with different chances of Angelman syndrome occurring again in a family.
Help determine clinical trial eligibility
Some clinical trials may have specific genotype requirements for participation.
Types of genetic tests
Different genetic tests look for different changes associated with Angelman syndrome. Some can confirm the diagnosis, while others provide additional information about the specific genotype.
Tests commonly used in Angelman syndrome diagnosis
DNA methylation testing
Individuals living with AS who have a deletion, UPD, or imprinting center defect (ICD), about 80% of individuals living with AS, have a specific DNA methylation pattern that can confirm the diagnosis of Angelman syndrome.
There are several methods used to test DNA methylation, including methylation-specific PCR (MS-PCR), methylation-sensitive high-resolution melting (MS-HRM), and methylation-sensitive multiplex ligation-dependent probe amplification (MS-MLPA).
MS-MLPA
MS-MLPA can check DNA methylation and look for deletions at the same time. It can confirm the diagnosis of AS for individuals with typical AS deletions, UPD, ICD Deletions, and ICD Epigenetic, and can provide the genotype for typical AS deletions and sometimes ICD Deletion genotypes.
UBE3A sequencing
About 10–15% of individuals living with Angelman syndrome have a variant in the sequence of the UBE3A gene, also called a mutation. Sequencing reads the gene to check whether all of the genetic material is present and in the correct order. If a variant is found in the maternal UBE3A gene that makes the UBE3A protein nonfunctional or less functional, the individual is said to have Mutation AS. UBE3A sequencing is usually done with a panel of genes or as part of WES/WGS sequencing.
Chromosomal microarray
Chromosomal microarray, also called CMA, CGH, or microarray, is a common test used to identify missing or extra pieces of DNA and is often one of the first tests performed when a person has developmental delays.
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 paternal chromosome, so methylation studies may also be needed. SNP-CMAs can also identify isodisomy UPD.
Whole exome or whole genome sequencing (WES/WGS)
Whole exome sequencing (WES) and whole genome sequencing (WGS) evaluate many genes at the same time and are typically used when a diagnosis is unclear or when a healthcare provider is considering several possible genetic conditions. WES/WGS are a type of sequencing.
WES looks primarily at the parts of genes that code for proteins, while WGS also evaluates DNA outside those regions. The way these tests are performed and analyzed can vary from laboratory to laboratory. Some WES/WGS tests may identify deletions associated with Angelman syndrome, and some may identify UPD when parental samples are included.
WES/WGS should detect UBE3A variants, but UBE3A may not always be completely analyzed when thousands of genes are being evaluated at once. Standard short-read WES/WGS cannot detect ICD Epigenetic.
If your loved one has already had WES or WGS: Ask your genetics team which Angelman syndrome genotypes were evaluated or ruled out by that specific test.
Tests that can help clarify the genotype
ICD Deletion testing
This testing is typically performed when methylation testing is consistent with Angelman syndrome but testing has not identified a 15q11.2-13 deletion or UPD. ICD Deletion testing may also be included as part of MS-MLPA.
UPD15 / microsatellite testing
This test compares markers found on chromosome 15 between the individual living with AS and that person’s parents to determine whether both chromosome 15s were inherited from the sperm.
Testing usually 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.
Other genetic tests you may encounter
FISH
FISH uses fluorescent tags that attach to specific locations on a chromosome to determine whether a section is missing or present.
FISH cannot determine the size of a deletion or whether it is on the maternal or paternal chromosome. It was used more commonly in the past; the original content notes that CMA or MLPA are now generally recommended instead because they can provide more information about the deletion.
Standard chromosome analysis (karyotype)
This test looks at chromosomes in a small number of cells under a microscope. It is designed to identify whole extra or missing chromosomes or large extra or missing pieces of chromosomes.
Because the deletion that commonly causes AS is not usually visible under the microscope, standard chromosome analysis cannot be used to diagnose AS. Most people with AS will have a normal standard chromosome analysis.
Long-read sequencing (LRS)
Long-read sequencing is a newer technology that evaluates the sequence of genes and can also analyze methylation. This means it can detect all AS genotypes in one test.
LRS is still mostly available in research laboratories, with relatively few clinical laboratories currently using this method.
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What a genetic test report may look like
Genetic reports can include the gene tested, the specific variant identified, and how the laboratory classifies that finding. Your genetics provider or genetic counselor can help explain what each part means.
If results are negative or unclear
A negative or inconclusive result does not always rule out Angelman syndrome. Different genetic tests look for different types of changes, so additional testing may be recommended depending on which tests have already been performed and what those results show.
Testing methods can vary from laboratory to laboratory, so asking your provider about the specific testing performed on your loved one is necessary.
Have questions about your genetic test results?
Questions to ask your provider
Genetic testing for AS can be complex, and it is not always clear what a result does or does not tell you. These questions can help you understand what testing has already been completed and whether anything else may be needed.
- What genetic testing has already been completed?
- Did the testing confirm Angelman syndrome?
- Did the testing identify the genotype?
- Is any additional testing recommended?
- What do these results mean for future pregnancies or other family members?
- If whole exome or whole genome sequencing was done, was the UBE3A gene well evaluated?
Continue learning
Learn about the different genetic causes of Angelman syndrome.