Dravet syndrome and the influence of the genome: Dr. Sanjay Sisodiya

Newswise — Reported, edited and produced by Nancy Volkers, ILAE communications officer

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Dravet syndrome is a rare, severe epilepsy caused by certain changes in the SCN1A gene. But people with Dravet also have a wide range of clinical characteristics that can't be fully explained by these changes. And not everyone with these changes develops Dravet syndrome. What else is going on? ILAE spoke with Dr. Sanjay Sisodiya about a recent publication on genomic influences in Dravet.

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Podcast Transcript

ILAE: Today, we're speaking with Dr. Sanjay Sisodiya about a recent study in the journal Brain. The study focused on genomic influences on phenotype in Dravet syndrome. You can find links to the study in the show notes and the transcript.

Well, thank you for joining us. If you'd like to introduce yourself to our listeners, that would be great.

[00:00:22] Dr. Sanjay Sisodiya: My name is Sanjay Sisodiya. I'm an adult, academic, clinical neurologist at the UCL Queen's Square Institute of Neurology and the National Hospital for Neurology and Neurosurgery. And I have an interest in difficult-to-treat epilepsies. Often, as you know, these are caused by rare genetic changes.

[00:00:45] ILAE: Great. So this paper that was recently published, it, it sounds like it sort of calls into question the idea that Dravet syndrome is monogenic. Did you have suspicions, or sort of, what motivated you to go in that direction and do that research?

[00:01:05] Dr. Sanjay Sisodiya: So as the number of people that we see in our service with Dravet syndrome has been increasing, as we receive more referrals from children becoming adults and going through the transition process into adult care, and as more adults are being diagnosed with the condition, what became apparent, I think, and I think probably has been apparent to pediatricians maybe for some time, is that the spectrum, the phenotypic spectrum in Dravet syndrome is wide.

So, for example, you may see somebody who is able to walk into clinic with a normal gait and is able to engage in basic conversation and, you know, has a variety of interests, may be able to go down to the shops to buy something, for example, and whose seizures may be relatively well controlled. And they have the same condition, the same core condition as somebody who maybe has a much more severe phenotype, who maybe, for example, has to be brought to clinic in a wheelchair, may not have the ability to communicate in any way, may have very frequent and severe seizures.

The core phenotype for both individuals can be the same. You'll see the same early history, and they both may have variants in SCN1A that are considered pathogenic using the appropriate guidelines, and yet they are so very different. And we see this, of course, for other rare genetic epilepsies, but I think it's most apparent in Dravet because I suppose, at least in my practice, we see more people with Dravet than most of the other rare epilepsies.

And so I suppose the question has always been, “Why is that?” And can we learn something from the people who've got less severe or more severe phenotypes that might help? That might help in understanding the condition and might help in its treatment.

We know that there are some factors that can influence this. For example, we know probably that the type of variant makes a contribution, but these factors that are known about don't explain everything or are not themselves explained. So for example, myoclonus occurring early seems to be a bad prognostic factor, but we don't know why, and why does myoclonus occur earlier?

Why is there this phenotypic spectrum? So what we thought we'd do with the advent of whole-genome sequencing is to ask the question of whether there might be variation across the rest of the genome that might be influencing the phenotype. And it's kind of not really that weird to think that, I think, because, of course, no single genetic variant acts by itself.

We are not, we're not the product of our genomes fully anyway, but neither are we the product of a single variant in our genome. It acts against the background of the whole rest of the genome. So, it didn't seem unreasonable to look at the whole of the rest of the genome and see whether we might find something else there that we could consider is influencing the phenotype.

[00:04:07] ILAE: So you had several groups that you compared in this study, you had a cohort of adults, I believe, with Dravet syndrome and then several. different control groups. Can you talk about those and why you chose those specific groups?

[00:04:22] Dr. Sanjay Sisodiya: Yes, so you can imagine that if you just compared a group of adults with Dravet syndrome with, let's say, healthy individuals, you're going to find genetic changes. You’d probably find a change in SCN1A. We picked all of the people in our study on the grounds they had a clinical diagnosis of Dravet syndrome with a pathogenic SCN1A variant. So you'd find that difference, obviously, and you know, and you find other differences that might simply reflect that the study group all had epilepsy.

So, we needed other control groups that would help us tease out the different elements here and allow us to focus on the variation that might be influencing the Dravet phenotype itself. And so, as you say, we had a number of control groups. We had a control group of people who had epilepsy but were known not to carry a pathogenic SCN1A variant, and we're able to create that cohort through the Genomics England (GEL) project, in which, of course, there are now, thousands of people who have epilepsy as their primary phenotype who have whole genome sequencing.

And we also used, again, through the Genomics England resource, a really important group of individuals who are not known to have epilepsy and who still carry a missense variant in SCN1A. So these are individuals who carry, in some cases, variants that have previously been associated with Dravet Syndrome, but they don't have Dravet Syndrome, and they don't seem to have epilepsy as far as we can tell.

So that really helped us tease out exactly what the SCN1A variants themselves might be doing. Now I have to add here that all of the cohorts were modest in size. So our study cohort was modest in size. And the number of people out there who might carry an SCN1A variant and have no apparent consequences is also small.

And we looked at people with missense variants in SCN1A. Because everyone in the GEL cohort who turned out to have a stop-gain, for example, in SCN1A, all turned out to have Dravet syndrome. So we didn't look at those people; we looked at people with missense variants. So those were the control groups that we were really interested in and we hoped would allow us to focus on what's going on in Dravet syndrome itself.

[00:06:38] ILAE: Great, thank you. In your opinion, what were the results that most stood out to you that maybe you were surprised by?

[00:06:48] Dr. Sanjay Sisodiya: Well, there were some, actually. So I think it's just important first to state that obviously this is, this is a pilot study, if you like. I think the findings are intriguing and potentially important. But obviously the number of people with Dravet syndrome we studied was small, 34 people, they were all adults. And for some of the analyses, we were only able to include people of European ancestry, because ancestry makes a difference to the findings from the test.

So it's important just to keep that in mind. And obviously it will be important to study these questions and findings in bigger cohorts to substantiate the findings. But we did find some things that were interesting.

So, and I suppose in summary, what we think is that it does appear at least in this cohort, background variation in the genome has a consequence. And so for example, what we found was, looking at rare variants, we found an individual who had a pathogenic variant in SCN1A, had a clinical history that fitted very well with Dravet syndrome, but also had focal seizures and a long history of focal seizures, and was known to have focal cortical dysplasia on their MRI brain scan. And this individual turned out to have a rare variant in DEPDC5 also present as well as the SCN1A variant. And through some modeling work, we concluded that that variant in DEPDC5 was likely to impact the function, disrupt the function of the protein. And although we weren't able to prove that, it seems likely that it would cause disruption to the entire pathway regulation, and therefore typically what you see with focal cortical dysplasia associated with DEPDC5 variants.

And we also saw that there was an over-representation of rare variants across a set of epilepsy genes in people with Dravet syndrome compared, for example, with people with epilepsy who did not carry SCN1A variants.

We also looked at common variation because, you know there's no reason to think that one type of variant or another should have a particular role, so we were interested also to look at common variation, and the way we did that was through the use of polygenic risk scores, which are a way of summating the effect of lots of individual variants, each of which might have a small effect, and you put them all together, and you might have a bigger effect that has some relevance.

So polygenic risk score work is well established now. It's making its way into clinical practice, for example, for cardiovascular diseases. So we were interested to see whether polygenic risk scores for a variety of traits were significantly different in people with Dravet syndrome compared with people with non-Dravet epilepsy.

And we hypothesized that the polygenic risk score for intellectual function would be lower in people with Dravet compared with people with epilepsy that's not Dravet. And we also hypothesized that the polygenic risk score for longevity would be reduced. We did some other testing as well, but these are just two examples.

And so we did find that the polygenic risk score for intellectual function was reduced in people with Dravet syndrome compared with people who had epilepsy that wasn't Dravet syndrome. And what that tells us, I think, is that actually whilst obviously the SCN1A variant and the epilepsy and disruption of developmental processes and the seizures themselves, maybe medications, have an effect on cognitive function, there is also a contribution from the common variant load that people have, because obviously that's not something that's required, it's there at the same time as the SCN1A variant and it wouldn't be something that we'd expect to change. So there is, there is a contribution from a polygenic background here.

What I think did surprise us was the longevity finding. So we hypothesized that the longevity polygenic risk score would be reduced because we know, for example, that Dravet syndrome is associated with a higher early mortality. And we were surprised to see that polygenic risk score for longevity was actually increased compared to the non-Dravet epilepsy cohort. And this was puzzling to begin with and I'm not sure that we fully answered this, that we fully understand why it's increased. One possibility is that the cohort we studied are all adults. And so might be considered to be, if you like, self-selected survivors. They have not succumbed to early mortality, they're all over the age of 20. And so maybe somehow they have an intrinsic resilience that is at least partly genomically driven, measured by the polygenic risk score for longevity.

And I think we obviously need to go on to test that by looking at bigger cohorts, but also cohorts which include a wider age range and include children. So there were some findings that we thought were surprising and that we want to explore further.

But overall, what we found, I think, was that there's evidence for both common and rare genetic variation beyond the SCN1A variant contributing to the overall phenotype, suggesting that the SCN1A variant acts against a background that's partly less resilient, as measured, for example, by the polygenic risk score for intelligence, but also in some ways more resilient, as measured by the polygenic risk score for longevity.

And this is where the SCN1A cohort of individuals who carried variants in SCN1A but didn't have epilepsy was also important, because we found actually the same things, that the polygenic risk score for intelligence was reduced in the Dravet cohort compared with the SCN1A cohort that didn't have epilepsy. Now that was a small study. It was a post hoc element of the study. And so we clearly need to look at that further, but it's a tantalizing result.

[00:12:49] ILAE: Well that's where I was going to go next; I think the paper said there were, there were five people who had SCN1A variants that were previously reported as being associated with various epilepsy syndromes, including Dravet, but they did not have epilepsy. That is intriguing, right? Because that implies that those variants, there's maybe not a one-to-one relationship that if you have these variants, you will therefore have an epilepsy syndrome.

[00:13:20] Dr. Sanjay Sisodiya: Absolutely. Yeah, I think that's exactly, that's exactly right. And that's why we wanted to study this cohort in particular.

The study was underpowered here, obviously, because there aren't that many people that we, you know, were able to find these variants without a history of epilepsy. I don't think we can be certain they never had febrile seizures, but we can be certain they don't have Dravet syndrome. And so there is…. the suggestion here is that the SCN1A variant by itself may not be sufficient.

Now, I think it's important to say these are still early, you know, early days, and we need to substantiate these findings. But what it does suggest is that maybe having the SCN1A variant by itself is not enough. And actually, we know that already from family studies, where there might be an SCN1A variant segregating in a family, and some members of that family might have Dravet syndrome, some people might have a milder epilepsy, and some people might not have anything at all.

And that's not always explained by mosaicism. There is something else going on. And I guess what we're arguing in this paper is that maybe part of what else is going on is background genomic variation at both the common and rare variant levels.

[00:14:26] ILAE: The paper talked about some of the challenges in exploring this additional genomic variation after you identify a plausible pathogenic variant. Can you talk about some of those challenges?

[00:14:39] Dr. Sanjay Sisodiya: So I mean, I think there are a whole range of challenges, actually. I think one important challenge that we should think about right at the start is how we think about Dravet syndrome. So the diagnosis is a clinical diagnosis. Provided you've got that early information, you can be relatively secure, I think, in making a clinical diagnosis of Dravet syndrome. And the ILAE, for example, has produced really helpful guidelines that assist with that. And then typically, of course, what we all do, because more and more people are picking up on this, so you request a genetic test and then you might find that there is an SCN1A variant that's reported by the laboratory.

So now you've got somebody with a typical history of Dravet syndrome with an SCN1A variant. And so you put the two together and you have a secure diagnosis, you think, with molecular support for Dravet syndrome. But what we never do, because of course for most people it's a really difficult thing to do, is test that SCN1A variant. We don't actually know much of the time what that SCN1A variant does. Does it cause loss of function? Does it cause gain of function? Does it cause something more complicated? Does it cause anything? We make the assumption that it does. We all do it, but actually we don't know for a fact, and I think that's a really important starting point for this, and that illustrates, I think, part of the difficulties we had with some of the other things.

So we found variants in a variety of other genes, and often the phenotypes associated with variants in those other genes overlap with Dravet syndrome. And then trying to dissect out what that variant is doing compared with the SCN1A variant can be really difficult. And you know, it would require more complicated functional studies. We didn't do those in this paper. And I think, you know, those are more difficult studies to do. There are people who are much more expert at it than I am. And trying to engage people to do those studies can itself be challenging because it's in a sense, not much in it for the research group. So there are challenges in this work.

And I think we need, if we want to take this further, we need to try and get better functional readouts for some of those other variants to be more secure that they're likely to be contributing to the phenotype.

[00:16:46] ILAE: So I know this is a pilot study, but imagining into the future, what is the significance of studies like this to something like personalized medicine, you know, tailoring treatment to a specific genetic variant, if that genetic variant isn't all that's contributing to the phenotype?

[00:17:10] Dr. Sanjay Sisodiya: I think that's a really important question. Of course, it's part of the motivation to do this, to see whether we could learn maybe from people with Dravet who have a less severe phenotype, and how that might inform us about how we might maybe change a more severe phenotype into a less severe phenotype.

Maybe, you know, background genomic variation might give us an insight into that. But I think this is an important point, as well as obviously thinking about what the SCN1A variant is or isn't doing, which we don't know most of the time. It is important because I think, whilst the effect sizes for many of the things that we saw were limited so we're not claiming, for example, that the polygenic risk score for intelligence is the sole reason or a really important reason why people might have cognitive difficulties with Dravet.

It's likely to be contributing something, and it's important to think about that, because, for example, we might have the idea that if we could fully control the seizures in this developmental and epileptic encephalopathy, and maybe we do that through new gene-based therapies, we might hope for significant improvements in other domains like cognitive function.

And of course, that can happen. We do see improvement in cognitive function with seizure control, but it may not be that we can fully address those other difficulties. The term DEE itself, of course, implies that there is a D element, a developmental element here that maybe is reversible. But I guess this helps us fill in that picture a little bit and think about what that D actually means. How does that D arise, that developmental aspect, and it may not be just the SCN1A variant. So I think it tells us a little bit about what we might expect or anticipate or hope for from newer treatments. And of course, if we find other variants, especially rare variants, that might be contributing to the phenotype, that might mean that we need to think about whether any treatments that affect that could also be relevant for an individual with Dravet syndrome.

So there are a number of different angles but really we need to, expand this studd, and in order to be able to kind of make firmer statements about draw firmer conclusions from this approach.

[00:19:14] ILAE: Thank you. Are there any takeaway messages for clinicians who treat people with Dravet syndrome or anything applicable yet? Or is this sort of just, you know, a pilot study and very theoretical, not really many clinical implications.

[00:19:34] Dr. Sanjay Sisodiya: I think that's a very good question. I guess one important thing which is not just purely an academic exercise, I think, is that we really need to think about what we mean by monogenic. And that's an important point to think about broadly, because I think if we consider an entity to be entirely monogenic, we focus all our efforts on that variant, we focus all our treatment developments on that, on variants in that gene. We may be doing people a disservice; we may be undermining our own treatment developments because we haven't really thought about the environment within which this variant is having its effect. So I think there are broader conceptual issues that we need to be thinking about that will be relevant in the longer term.

I think in terms of practical management right now, I don't think that it should change the approach for somebody who's got a clinical diagnosis of Dravet syndrome with or without an SCN1A variant. There are well-established guidelines for how best to help somebody in that situation. And I don't think this study changes those.

But I do think it means that if the phenotype does seem maybe not entirely fitting with that of Dravet syndrome or seems to be Dravet syndrome "plus", we should not assume that that finding in that patient means we have to broaden the envelope of what we consider to be Dravet, and what we allow within the spectrum of Dravet.

We're always doing that. We find a gene and it's usually, you know, reported first in a few individuals, then somebody else finds a variant in that gene in another individual who's got a slightly different phenotype, and so the phenotype continues to broaden. And at some point, I think it must be that it can't all be that single gene itself, and we're bringing in phenotypes related to other variation.

And I think one thing to think about is that if the phenotype doesn't seem to fit completely, or if there are other features, clinically or investigations, it's worth thinking again, actually, because people do have more than one variant. We're always, you know, we’ve kind of been brought up to think, “One variant found, that's the end of the genetic testing. Let's get on with the next step.” And most of the time that's probably right, but it might not always be right. So if somebody's got something else, we should think about that.

And I think this applies, for example, to the focal cortical dysplasia. There are previous reports of people with Dravet syndrome and SCN1A variant who have been found to have focal cortical dysplasia. And that's been attributed to the SCN1A variant. Difficult, I think, maybe biologically to think how that might happen. But I think what this means is we should look, because maybe they've got another variant. Maybe they've got a germline variant in DEPDC5, or maybe they've got a somatic variant. More difficult to access, obviously.

But I think it means that we shouldn't always think that once we’ve found the variant, that's the end of the story.

[00:22:25] ILAE: Thank you. As far as this line of research goes, do you have plans or ideal plans for where to take it in the future?

[00:22:35] Dr. Sanjay Sisodiya: Absolutely. So we are now studying a much bigger cohort of people with Dravet syndrome along the same lines.

And so I think that's where we're going next is really to see what we find in a bigger cohort and whether we can substantiate these findings and also undertake novel analyses that a bigger cohort will permit, which you can't do with a smaller cohort because it just doesn't make any sense. The power's too low. So I think that's an important thing.

And also, I think to see whether this is a general phenomenon, is this just Dravet syndrome for which this applies, or maybe this is a broader phenomenon, we don't know. So I think there are lots of questions that this work opens up and we're looking forward to trying to address those.

[00:23:15] ILAE: Yeah, it's very intriguing. Are you able to study a cohort of younger children with Dravet to get at that longevity issue?

[00:23:25] Dr. Sanjay Sisodiya: Yeah, that's one of the things that we are now looking at. And I think it'll be really interesting to see what happens with that longevity PRS, whether it's still elevated for a cohort which includes children, or whether there's some kind of gradient, which depends on, you know, obviously it doesn't change with age, but maybe we'll see different polygenic risk score profiles in a pediatric population.

We'll have to see what emerges.

[00:23:50] ILAE: Is there anything else you wanted to add that we didn't cover?

[00:23:56] Dr. Sanjay Sisodiya: I think it really is, from my perspective, this is beginning to help address is the question of what is monogenic, and what do we mean by penetrance and expressivity. These have been really useful operational terms in the genetics field, but there must be a basis to those terms, there must be some mechanism, some reason. That we see these things, and there may be many reasons, and I'm not saying that the background genomic variation is the only one, but I think it's, you know, we can now get a handle on that. And that can only help us understand these conditions better and hopefully in the longer term improve treatments.

I think we are at the very start of this process. You know, we are literally scratching the surface. It's been fantastic in terms of the story up to this point of the description of Dravet syndrome, from astute clinical observation to the discovery of the gene, to models, to organoids, all kinds of things. It's been a really fantastic story, I think. Really helps us understand what's going on, but it is still the start of the story. I guess we're thinking, let's just take this one step at a time and handle what we can, you know, and the next step is let's look at the rest of the coding genome, but there's the whole of the non-coding genome too. And then there's the epigenome and all sorts of other things. And we're just going to take this one step at a time.