Angelman Syndrome Genetics 101

Quick Overview

Angelman Syndrome is a genetic disorder that can be caused by different types of problems with chromosome alignment. The most common types are type 1 and type 2 deletions, which involve missing pieces of chromosome 15. Type 1 is slightly more common and more severe, but the differences between the two are not statistically significant. The syndrome can also be caused by a larger, rarer deletion. Diagnosis is made through chromosomal testing, which can identify missing or extra pieces across all chromosomes. The syndrome is unique in that it matters whether the missing part is from the mother’s or father’s chromosome. This is determined through methylation testing. The syndrome is also associated with problems with the GABA-A receptor, which is important for response to the inhibitory neurotransmitter GABA. This could explain some of the symptoms of the syndrome, such as seizures, decreased need for sleep, hyperactivity, and anxiety. Current treatments are supportive, but gene therapy is being explored as a potential way to fix the original genetic change that causes the syndrome.

Understanding Chromosome Misalignment

It’s a really, really good question. There are different types of problems with alignment and depending on where that occurs, you could have a bigger piece missing or a slightly smaller piece missing. When we think about chromosomes, a megabase is a million base pairs, so a million of those letters, A, C, G, or T. And when we look at the chromosome 15, where these replicated regions are, those are all the regions where you could have misalignment.

Type 1 and Type 2 Deletions

The typical type 1 deletion, which is about 6 megabases, goes from break point 1 all the way to break point 3. So across the whole chromosome 15 in this region. And type 2 goes from break point 2 to break point 3. So it’s slightly smaller, it’s about 4.5 or 5 megabases for the type 2.

The Importance of Testing

On chromosomal testing, it depends how you were diagnosed. We used to do a test called FISH, which is… Yeah. So FISH is basically a single one of these many probes, so it’s getting at almost a single letter. It’s a little bit bigger region than that, but think of it as just targeting a single letter and looking for a missing portion.

Understanding Angelman and Prader-Willi Syndromes

You all might know this, but Prader-Willi syndrome is caused by a missing part of dad’s copy of chromosome 15. And so all the chromosomal testing can tell us is that there’s a missing part, but it can’t distinguish whether there’s a missing part between mom’s chromosome or dad’s.

The Role of UBE3A

Part of the solution is UBE3A, right? But is it actually not the part of the solution of that UBE3A? Is it part of the solution of the SNRPN gene? Or is it separate? No, so the SNRPN gene goes all the way across the region, because it’s the control region, but if you look at the chromosomal region, there are many different genes within this region, and one of those genes is UBE3A.

The Impact of Gene Therapy

So I think a lot of people with Angelman Syndrome, for example, don’t have developmental delays and haven’t developed speech. And so the goal is that we target the key features and in addition treat some of these additional features that we’re now recognizing. So the hope is that it would impact everything.

Conclusion

There’s a difference between supportive therapy and the gene therapy. So the goal of the gene therapy is to fix the original genetic change that caused the Angelman Syndrome. And that’s a very different thing than talking about some of the medications and things that we use to help. But there’s lots of exciting things coming. Anyone else have questions about genetics? Okay. Well, thank you all for coming.