AS Genotypes: Mosaic

Mosaic AS is a rare genotype. A person with mosaicism has a mixture of cells that make UBE3A and cells that do not make UBE3A in the body. Most reported cases have an estimated 5-20% of cells that have maternal expression, though between 1-40% are reported.

Mosaicism is most often associated with a methylation ICD, but it has been reported with deletions as well. Mosaicism typically occurs after conception, during the development of an embryo.  Consequently, the chance for a future child to have mosiacism for AS is predicted to be very low.   

Mosaicism actually played a key role in our understanding of why we believe Angelman syndrome can be cured.

In 2004, the journal Human Molecular Genetics published a paper reporting on a subset of individuals with Angelman syndrome who were expressing a small percentage of UBE3A. That small amount was making a big difference. A person expressing 1-5% of UBE3A had few to no seizures; was ambulatory, and even had some speech. 20% UBE3A expression meant no seizures, minimal to no ataxia and speech in sentences. What this meant was that our loved ones didn’t need to get to 100% UBE3A expression, or even anything close. Bottom line: A little UBE3A protein goes a long way.

This also means that individuals living with mosaic AS present a specific complication for researchers, regulators and those in charge of clinical trials inclusion at pharmaceutical companies—who are concerned that a treatment might cause overexpression in the subset of cells that we know are expressing the maternal UBE3A gene. At FAST, we believe this is a minority of cells (1-20% generally), and thus should not be considered a serious concern, which is the position we assert to those in the research and pharmaceutical spaces. We are fighting every day to make sure no genotype, not even our rarest, is left behind.

Connect with other AS Mosaic 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.