AS Genotypes: Deletion

The most common cause of AS is that the UBE3A gene is missing, or deleted, from the maternal copy of chromosome 15.   Because the maternal UBE3A gene is missing and the paternal UBE3A gene is turned off, a person with a deletion of the maternal UBE3A gene does not make any UBE3A protein.

The information on this page is about the chromosome deletion that commonly causes AS.  This is also referred to as deletion of 15q11.2-q13 (this naming provides the exact location of the deletion on the chromosome) or as deletion + AS.  AS can be caused by other smaller deletions, including a deletion of the imprinting center or a deletion within the UBE3A gene.  The imprinting center deletion and the deletion of part of the UBE3A gene are NOT the same as the deletion discussed here.  An imprinting center deletion is considered an imprinting center defect (ICD); A deletion within the UBE3A gene is considered a Mutation.  If you’re not certain which genotype your loved one lives with, please reach out to FAST’s genetic counselor to discuss.

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Individuals living with AS deletions are often missing not just UBE3A but also 8-12 other genes. This means they are missing 5-6 MILLION base pairs of DNA on the maternal chromosome 15. The other missing genes also contribute to tonic inhibition, seizures, lighter coloring, and more. All together, this makes the features of those living with AS deletion generally more severe than the other genotypes.

Most individuals living with AS deletions have either a Class 1 or Class 2 deletion (also sometimes referred to as Type 1 or Type 2 deletion).   The class is determined by where the deletion starts and where it ends.  Class 1 deletions start at breakpoint 1 (BP1) in this figure below and end at breakpoint 3, for a total of about 6 million base pairs deleted, while Class 2 deletions start at breakpoint 2 and extend to breakpoint 3 with about 5 million base pairs deleted.   About half of individuals who are living with deletion AS have a Class 2 deletion, and about 40% have a Class 1 deletion.  Most of the remaining 10% with deletion AS have a deletion that is larger, extending to breakpoints 4,5, or 6.   The Class 1 deletion includes more genes than the Class 2 deletion. However, it is not clear whether missing the additional genes can cause more severe or different symptoms in AS.  Several studies have tried to understand this and have had conflicting results.

In most individuals, the deletion of UBE3A and the surrounding genes was a random event and NOT inherited from a parent.  The deletion actually occurs when the mother’s eggs are developing, which happens before the mother is even born!  However, in rare cases, the deletion happens during the formation of the egg because of a chromosome difference that the mother carries.  This chromosomal difference increases the possibility of a deletion occurring when eggs are made.  Consequently, chromosomal testing of the mother is recommended. 

If the mother has chromosomal testing that is typical, the chance for a future child to have the deletion that causes AS is predicted to be less than 1%.  This means that more than 99% of the time, future children will not have the deletion that causes AS.  The chance is not zero because there have been rare cases reported where the woman had multiple eggs with the deletion or actually carried the deletion in some of her body cells. 

All the pharmaceutical companies in our space have stated that they want to have the most consistent group for the earliest phases of clinical trials (Phase 1/2), and in many cases they want the most severely affected to start with. That is generally considered to be those with deletions.

All 4 of the current trials underway are enrolling patients with AS deletions, including Class I and Class II deletions. Go to the Current Pipeline page to learn more about them.

Connect with other AS Deletion families by writing to us here: community@cureangelman.org

Still have questions?

If you are wondering about your specific chance to have a child with a genetic variant that causes AS, it is very important to consult a genetics professional like a genetic counselor or geneticist. The chance varies depending upon the test results of the person living with AS and the testing that was performed on the parent(s). The information provided here may be helpful but it is not specific to your family and is not meant to replace genetic counseling.