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
FOUR GENETIC DIAGNOSES
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
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.)
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.
UBE3A AND RECURRENCE RISK
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
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,
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.
WHY AND HOW DO MUTATIONS HAPPEN?
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