Angelman syndrome is a rare genetic disorder characterized by mental and physical developmental delays. Children with this disorder may show symptoms such as muscle weakness as early as six months of age.
What causes Angelman syndrome?
Angelman syndrome is caused by mutations in a gene called UBE3A, which is located on chromosome 15. People inherit two copies of the gene, one from each parent, but in some areas of the brain, only the maternal copy of the UBE3A gene is turned on. If this copy is lost due to a mutation, the person will have no functional copies of the gene in some parts of their brain.
Different genetic mechanisms can cause the inactivation of UBE3A, which means that it may take several genetic tests to confirm a diagnosis of Angelman syndrome.
What is genetic testing?
A genetic test detects changes in genes that may indicate the cause of a disease. To perform a genetic test, a small blood sample is taken from the patient in a hospital or clinic, and then it’s sent to a laboratory that performs the genetic tests requested by the patient’s physician. It may take several weeks or months to get the results back. The physician, and perhaps a genetic counselor, will then meet with the patient’s parents or caregivers to discuss the results.
What genetic tests are used to detect Angelman syndrome?
A number of genetic tests may be required to confirm a diagnosis of Angelman syndrome. These include:
Cytogenetic analysis is a test that analyzes a patient’s chromosomes, and can detect changes in their numbers and rearrangements where one chromosome has become “stuck” to another. This test alone does not give sufficient detail for diagnosis but can be used to rule out other diseases that have symptoms similar to Angelman syndrome.
DNA methylation test
About 80% of Angelman syndrome patients can be identified with a chromosome 15 activity test. This test measures a DNA modification called DNA methylation, which allows scientists to determine which portions of the patient’s DNA came from the father or mother, and whether the UBE3A gene is missing in the maternal portion of DNA.
In combination with a DNA methylation test, a fluorescence in situ hybridization (FISH) or comparative genomic hybridization test can be used to determine whether portions of a chromosome are missing. A missing UBE3A gene can confirm a diagnosis of Angelman syndrome.
Polymerase chain reaction assay
Some patients may have inherited both copies of chromosome 15 from their father and no copies from their mother. This is called uniparental disomy. Without a maternal copy of UBE3A, the person will develop Angelman syndrome.
If a patient tests positive for Angelman syndrome in the DNA methylation test, but their FISH test is negative, the patient’s physician can request a polymerase chain reaction (PCR) assay. In this test, the patient’s DNA is compared to both of their parents’ DNA, which means that the parents must also provide blood samples. The test determines whether the patient has a maternal copy of chromosome 15 (and of the maternal UBE3A gene). If not, the patient will be diagnosed with Angelman syndrome. The PCR assay can also be used to identify small mutations or deletions in the child’s chromosome 15.
In addition, the PCR test can detect if a patient inherits an Angelman syndrome-causing mutation in the UBE3A gene from their mother, even if the mother has no symptoms of the disease.
In very rare cases, Angelman syndrome can be caused by UBE3A gene mutations that do not inactivate the gene but affect the function of the protein that is made from the gene. If the other tests are negative, the precise DNA sequence of the UBE3A gene can be examined to identify any mutations. This DNA sequencing test is required for the diagnosis in about 10% of Angelman syndrome cases.
Last updated: September 8, 2019
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