GeneticaLens-The Angelman Project - Genetics
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What is Angelman syndrome?
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A chromosome consists of DNA, which is a length of chemicals that make up a code. This code is our genetic information. A gene is a length of DNA in a chromosome. Each cell of our body contains 23 pairs of chromosomes, whereby one of each pair comes from the mother, the other from the father. Angelman syndrome is caused by a malfunction of the gene UBE3A in the maternal chromosome #15.


To date, there are four known genetic causes for AS which can be determined by genetic testing. Even though there are some variations in the symptoms, these four distinctive diagnoses all cause the same syndrome. The reason for that is that these four diagnoses all affect the gene UBE3A on chromosome #15, preventing it from functioning properly.
The four different diagnoses are as follows:

This diagnosis accounts for 70% of people with Angelman syndrome. Individuals with a deletion have a piece missing on their maternal chromosome #15. (Deletions on the paternal chromosome #15 are the cause for the disorder Prader Willi) This is a spontaneous mutation which is not hereditary. A deletion can be detected using the FISH (Fluorescent In Situ Hybridisation) test. (For our list of subjects with a deletion, click here.)

Uniparental disomy (UPD)
An individual with UPD has two chromosomes #15 from their father, and none from their mother. They are thus lacking the crucial UBE3A gene coming from the mother. This usually happens if there is no chromosome #15 in the egg, so the chromosome #15 in the sperm duplicates itself so the baby will have the right number of chromosomes. UPD accounts for 2-3% of the Angelman population. Again, this mutation is spontaneous and not hereditary. (For our list of subjects with UPD, click here.)

Sometimes the mother's chromosome #15 happens to be "blank," in which case it copies the father's chromosome #15. This process is called imprinting. Again, this mutation is spontaneous and not hereditary. (For our list of subjects with an imprinting defect, click here.)

UBE3A Mutation
Malfunction of the UBE3A gene on the maternal chromosome #15 seems to be the cause of Angelman syndrome. In the case of a UBE3A mutation, there is a mistake in the genetic code of the UBE3A gene. This can happen anywhere on the length of the gene, however, two specific regions (called Exon9 and Exon16) seem to be more prone to mutations. The UBE3A mutation is hereditary, which accounts for multiple AS births within one family (see UBE3A and recurrence risk). A UBE3A mutation can only be detected using the UBE3A test. (For our list of subjects with a UBE3A mutation, click here.)

What if the genetic tests are negative?
There are some people who have none of the above mentioned genetic defects, but they show the symptoms of Angelman syndrome. In that case, the diagnosis remains clinical until genetics researchers find tests which can account for those diagnoses. (For our list of subjects with a clinical diagnosis only, click here.)


The FISH test
Because a string of DNA is very long, it was important to find a method to hone in on the area on chromosome #15 that is important for AS. What the FISH (Fluorescent In Situ Hybridization) test does, is light up this critical area on chromosome #15, so it stands out immediately. However, if there is a deletion, it won't light up because it's absent, so it is apparent very quickly whether a deletion is present or not.

The UBE3A test
The UBE3A test is much more complicated and time-consuming than the FISH test. The critical area on chromosome #15 is present, and the only difference between an affected and a "normal" chromosome is a small variation in the genetic code on the UBE3A gene, which is very long. The entire length of the UBE3A gene has to be "proof-read" for mistakes in the code, a process that takes several weeks and has to be done by a geneticist, not by a machine. This explains the cost of the test, and why it is only done after the other, more easily detectable diagnoses have been ruled out.


As we mentioned above, a UBE3A mutation only causes Angelman syndrome if it appears on the chromosome #15 coming from the mother. However, if a woman has a UBE3A mutation on the chromosome #15 coming from the father, then she could in turn pass it on to her children, who would then have the mutation on their maternal chromosome #15 and hence have Angelman syndrome. Similarly, if a man has a UBE3A mutation on his paternal chromosome #15, his children would not have Angelman syndrome. But they again could be carriers of the mutation, and if a daughter was a carrier, she could then pass it on to one of her children. Or if a son was a carrier, then one of his grandchildren could have AS.

The following graphic shows how the UBE3A mutation can be passed on from generation to generation. A square signifies a man, a circle a woman. The black dot means that the mutation is present in the paternal chromosome #15, and a black circle or square means that this person has AS (i.e. that the mutation is present in the maternal chromosome #15).

UBE3A Mutation

This explains why some families have several children with AS, or why AS sometimes appears in distant branches of the same family. If you would like to know more about families with multiple AS births, click here.

This example shows how important it is to get a genetic diagnosis. If a case of Angelman syndrome caused by a UBE3A mutation is present in your family, then there is a chance that it might occur again at some point, even if it is in the distant future.


Whenever a new cell is created in our body, the DNA in the ³mother cell² makes a copy of itself for the new cell. It is very common that little mistakes happen in this process, but our DNA has a built-in repair mechanism that replaces the faulty piece with a correct piece. However, this repair mechanism doesnıt always work, and especially during the egg and sperm production, mutations are quite common. Luckily, in most cases, ³faulty² eggs and sperms usually donıt survive.

Sometimes parents wonder whether they did something to cause AS in their children. It is true that intense radiation, for example, can cause mutations to occur with a higher frequency. But in most cases, mutations are a completely natural occurrence and have nothing to do with having gotten an x-ray, for example.

Note: this is based on an interview with Jill Clayton-Smith. CLICK HERE to read her chapter: Genetic Counseling for Angelman Syndrome (AS)

Troy - (deletion +)
Troy (deletion +)

Oriel - (Imprinting)
Oriel (Imprinting)

Kaitlyn (UPD)
Kaitlyn (UPD)

Sai Kit (UBE3A)
Sai Kit or Min (UBE3A)

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