In the largest genetic analysis performed to date, coordinated by the International League Against Epilepsy (ILAE) and published in Nature Genetics, researchers from around the world sought to advance our knowledge of why epilepsy develops and potentially inform the development of new treatments for the condition. The researchers identified 26 distinct areas in our DNA that appear to be involved in epilepsy. This included 19 which are specific to a particular form of epilepsy called ‘genetic generalized epilepsy’ (GGE). They were also able to point to 29 genes that are probably contributing to epilepsy within these DNA regions.
The scientists found that the genetic picture was quite different when comparing distinct types of epilepsy, in particular when “focal” and “generalized” epilepsies were compared. The results also suggested that proteins that carry electrical impulse across the gaps between neurons in our brain make up some of the risk for generalized forms of epilepsy. This webinar will discuss the results of this genetic analysis in greater detail.
Dr. Samuel Berkovic is Laureate Professor in the Department of Medicine, University of Melbourne, and Director of the Epilepsy Research Centre at Austin Health. He is a clinical neurologist and clinical researcher with a special interest in establishing close research links with basic scientists. His work with Laureate Professor Ingrid Scheffer, together with molecular genetic collaborators in Adelaide and Germany, discovered the first gene for epilepsy in 1995 and subsequently, he has been central to the discovery of many epilepsy genes. He is currently leading EPI25, a global initiative with the Broad Institute at Harvard University to sequence over 25,000 individuals with epilepsy and was a member of the Steering Committee for CURE Epilepsy’s Epilepsy Genetics Initiative (EGI).
Yeah, so it depends when you ask me. If you would’ve asked me five years ago, we weren’t even dreaming of doing regular whole genome sequencing because it was so expensive and now it’s sort of tractable. One of the problems is that you’ve got to do it, but then you’ve got to analyze it. So in a lab, in a center where one has a research lab and one has Bioinformaticians, we now go for a whole genome sequencing. You get all the information, you can look at it quickly, but then you can look at it again and again as the years go by. Panels are limited because you only find what you look for, but they’re also relatively efficient. So it’s not a one-size-fits-all answer. It really depends on your patient, the circumstances you’re in and the sort of question you’re asking. I’m sorry, I can’t be more definitive about that, but that’s the pragmatics about how it works.
Okay, so as you’ve defined it, VUS’s are variants of unknown significance. It does not apply to the common variants. As I said, each of us have got 10,000 or so of these. So they’re not things that are reported in genetic testing. They are reported where people have done whole exome sequencing or whole genome sequencing and looked at the particular genes. And there are some changes or variants that occur in those studies that are instantly recognizable as important. Why would they be instantly recognizable as important or first that they’ve been seen in other patients with a similar disorder? That’s probably the strongest evidence. So there are now excellent databases that the genomics people look up and you get, for example, a change in SCN1A, perhaps a child who you think has Dravet syndrome and you go to the databases and there it is. There are multiple reports of this. So bingo, that’s the answer. And this is a variant that is significant.
However, you may find, and we’ll just stick with SCN1A to keep it simple, you may find a variant that has never been reported before. And here you’ve got to be careful because just because it’s a variant doesn’t mean it is significant and may be of unknown significance. So you have to be very careful there not to say, well, look, this patient’s got to change in this gene and therefore it must be significant. Big mistakes can happen with that. You’ve got to really validate that there’s a case for saying it’s significant. So the evidence for that is, I’ve already mentioned, if it’s been seen before. Secondly, if it occurs in a part of the gene or part of the protein that’s known to be really important for function, then you’ve got a sort of stronger case for it.
And sometimes, but this is sort of research testing and not available usually clinically, is that you can do so-called functional testing and actually measure the effect of the change in the lab. Now, this is the only way we used to have to do it. There are now incredibly powerful programs that can predict what might happen to a gene. And many of the people on the webinar might be aware that the Nobel Prize for chemistry… For medicine, sorry, was given to a group of scientists that developed what we called AlphaFold or what they called AlphaFold, which predicts the structure of all our proteins. So programs such as this can sort of tell us what the effect of a variant may be on the protein. Now we’re not at the stage yet where you go Dr. AlphaFold, tell you if it’s likely be important, but these are the tools now that labs have to build a case that it’s important.
But I appreciate that it’s hard for patients and families to integrate or comprehend what VUS means because it’s written there on the piece of paper, it’s written there on the genetic report, it’s there. But just like MRIs, there are MRI changes that are absolutely definitive. You see a focal cortical dysplasia, you see hippocampal sclerosis. There are also changes on MRI in people with epilepsy that are of dubious or uncertain significance. So it’s true in genetics as well. So I hope that helps. It’s a bit of a roundabout explanation, but that’s sort of how the situation sits. And I think the good news is the proportion of VUSs that we report or see is going down simply because of the fact that these databases are growing and the genetics community sort of worldwide I think is good at reporting information where they found something that they believe is important, and if the same variant in your patient, one has got a match.
Yes and no. So the association of JME with Doose syndrome is unlikely but not heard of, but it is unlikely. And unfortunately you can have well, both Doose syndrome and JME. Doose syndrome has some single gene variants, but may well be a polygenic disorder also, and JME certainly is. So unfortunately the genetic lightning might’ve struck twice in this family, unfortunately in different ways, or there may be some other modifying factors. I discussed the polygenic risk score as one way of looking at that, but both answers are possible that they are genetic related or unrelated. But because that’s an unusual combination, I would’ve thought more likely unrelated, but one can’t say for sure.
The heights of the peak on that Manhattan plot, those individual scenes that sort of describe the effect size, how big an effect that particular variant has. So these are computed relatively simply. I mean, you need a Bioinformatician to do it, but you take each gene that is significant or above a certain threshold and multiply it by its so-called effect size, which in simple terms is the height of those peaks and sum them all together.
POLG is a polymerase gamma, which is a gene related to the mitochondrial system, which are the powerhouses of cells where we break down glucose and other nutrients for them to do their job. It is a rare cause of epilepsy, a quite rare cause of epilepsy, but it’s a very important one because it has important treatment applications. So in people with POLG mutations, the drug sodium valproate or valproic acid as it’s known in the US, can have nasty adverse effects. And that drug needs to be avoided in people with POLG mutations. But it is rare. But on the other hand, it’s also important for the neurologist to recognize.
It depends on the disorder. For example, in 2024, the role of doing genetic testing through a gene testing company for something like Juvenile Myoclonic Epilepsy or Regular Temporal Lobe Epilepsy is pretty low. And I think it’d be hard to mount an argument. However, children with developmental and epileptic encephalopathies grow up and many of them are seen by adult neurologists, if they survive, and they live often somewhat limited lives. And again, finding out the cause in them can sometimes make a difference.
For example, the best recognized one of this is unrecognized Dravet syndrome, which is a condition that adult neurologists are not necessarily that familiar with, and the child is just sort of regarded as somebody with epilepsy and intellectual disability. But in fact, if you pick through it, they’ve got the characteristic evolution of Dravet syndrome and what do you know, they’re on carbamazepine or oxcarbazepine, drugs which make them worse, or phenytoin. So recognizing the right diagnosis can get them put on drugs that are known to be better for that. And as we know, there are now some much more specific treatments for Dravet syndrome, so it can make a difference. So look, I think it needs to be tailored to the case. I don’t think we’re at the stage where we want to do it willy-nilly on people with epilepsy, but there are specific situations where it can be very valuable.
That’s a summary of it. So I’ve already given the example of Dravet syndrome and there are other genetic disorders where it’s known that some drugs work well and some don’t work so well or indeed may make the patient worse. There’s also a field of pharmacogenomics, which is a field where genetic changes alter the way our bodies handle the drugs, and that can be used to help tailor a medication. One would have to say that the impact of that, and we’ve been talking about pharmacogenomics for 20 years, has been less than expected. The one major exception to that has been prediction of side effects, and in particular Stevens-Johnson syndrome.
So for example, it’s known that a particular genetic change, which is of higher prevalence in people of East Asian origin, predisposes you to Stevens-Johnson syndrome with those drugs with carbamazepine and to a lesser extent, oxcarbazepine and phenytoin. So here, if one has a patient of East Asian extraction and there’s black box warnings for this, that you ought to test for the particular genetic variants that predispose to this sometimes fatal side effect. So that is another sort of important use, but it’s not something that one thinks about with every patient.
No, not to my knowledge. And again, the story with SNPs is that we’re largely not at the stage where we can narrow it down to a particular SNP. It’s sort of a large group of SNPs that are put together, and these are aggregated in the polygenic risk scores. I’m not aware of anything that’s been shown to be specific to epilepsy with eyelid myoclonia, and I doubt that we’ll find it, but it may change.
The information contained herein is provided for general information only and does not offer medical advice or recommendations. Individuals should not rely on this information as a substitute for consultations with qualified healthcare professionals who are familiar with individual medical conditions and needs. CURE Epilepsy strongly recommends that care and treatment decisions related to epilepsy and any other medical condition be made in consultation with a patient’s physician or other qualified healthcare professionals who are familiar with the individual’s specific health situation.