Angelman Syndrome: ICD
The imprinting center defect (ICD) affects 2-3% of individuals living with AS
What it means
The mother’s chromosome 15 is incorrectly marked like a father’s chromosome 15, which turns off the UBE3A gene in the brain and causes Angelman syndrome.
How common is it
About 2-3% of individuals living with AS have ICD.
Is it inherited?
Depends on the cause of the ICD.
What is ICD Angelman syndrome?
When there is an ICD, the imprinting center doesn't work. As a result, the UBE3A gene is turned off on the maternal chromosome 15 when it is supposed to be on. Because the paternal UBE3A gene is always turned off in neurons, an ICD on the maternal chromosome 15 results in no UBE3A protein being made. This can also be called an imprinting defect (ID).
A simple way to think about it.
The maternal copy of UBE3A is incorrectly turned off. The paternal copy is naturally silenced in the brain.
That is why an imprinting center defect (ICD) can cause Angelman syndrome.
What can ICD mean for my loved one?
There are two types of ICD AS, ICD Deletion and ICD Epigenetic. Knowing which type your loved one lives with can help for a variety of reasons.
ICD Deletion:
With an ICD Deletion, a very small piece of DNA is missing from the imprinting center, the part of chromosome 15 that helps set the correct maternal or paternal label.
This missing piece causes the mother’s chromosome 15 to act like it came from the father. As a result, the maternal UBE3A gene is turned off in the brain.
ICD Epigenetic:
With ICD Epigenetic, the imprinting center is present, but its “labeling” process did not work correctly. There may be no missing piece of DNA or detectable change in the imprinting center sequence.
This type can also be called an ICD non-deletion or methylation-defect AS. In some people, the change affects only some cells in the body. This is called mosaicism.
Questions about ICD AS?
Your genetic report may help you understand the type of ICD. FAST’s genetic counselor, Niki Armstrong, can help you obtain and understand it.
Schedule a 1:1 AppointmentCould this happen again in our family?
ICD Epigenetic AS is not known to be inherited. However, ICD Deletion is often inherited from the mother who also carries the ICD Deletion. Consequently, testing the mother for the ICD Deletion is important.
Maternal Testing for the ICD Deletion (15% of ICD AS)
Negative: ICD Deletion randomly occurred during the formation of the egg and was NOT inherited
Mother carries the ICD Deletion
Chance for ICD Deletion AS in future pregnancies is <1%.
Chance for ICD Deletion AS in each future pregnancy is 50%.
Other family members do NOT have an increased chance to have a child with ICD Deletion AS.
Other family members may carry the deletion and have an increased chance to have a child or grandchild with ICD Deletion AS. They may wish to consider ICD Deletion testing to understand their chances.
*Reference: Horsthemke B, Bulting, K: Genomic Imprinting an imprinting defects in humans. Adv Genet 61:225-246 (2008).
Do you need maternal testing for ICD Epigenetic?
No, maternal testing is not typically recommended. In most cases, ICD Epigenetic AS is caused by random event that occurred early in the development of an embryo. The chance for a future child to have ICD Epigenetic AS is predicted to less than 1%. This means that more than 99% of the time, future children will not have ICD Epigenetic AS.
How is ICD AS different from other AS genotypes?
ICD Angelman syndrome is similar to UPD Angelman syndrome, so the two are often grouped together. In both, the brain does not have an active maternal copy of UBE3A.
Unlike Deletion AS, most people with ICD AS do not have a large missing section of chromosome 15. With Epigenetic ICD AS, no DNA is missing; with ICD Deletion AS, only a very small piece is missing. Because fewer genes are affected, people living with ICD AS may have less severe features than people living with Deletion AS.
Most ICD-related features are caused by the lack of UBE3A in the brain. However, people with ICD may make extra amounts of proteins from genes that are normally active only on the father’s chromosome. This may contribute to increased appetite or a higher risk of weight gain.
ICD can look very different from one person to another. Some people with Epigenetic ICD AS have mosaicism, meaning some brain cells make UBE3A protein while others do not. This may affect how Angelman syndrome shows up for that individual.
Are there clinical trials for individuals living with ICD AS?
Each clinical trial has its own criteria for participating. Some trials are enrolling individuals living with ICD AS and some are not.
For potential therapeutics that aim to turn on the paternal UBE3A gene (like ASOs), researchers may need to consider differences between Deletion AS, where there is only one paternal copy of UBE3A to turn on, and ICD AS, where there are TWO copies of UBE3A to turn on. This has sometimes led to early phase trials not including ICD AS. FAST is dedicated to the development of transformative therapies for ALL individuals living with us!
