Plus, discover the latest in genetic testing advances in this episode of our Seizing Life podcast.

To learn more about CURE Epilepsy’s EGI initiative please visit the links below.

EGI Overview

EGI Initiative

Audience Q&A with Dr. Dan Lowenstein

What are the different types of genetic tests that are out there right now?

The most common test involves taking a taking DNA, taking a blood sample and applying it to what we call an array. An array is essentially a matrix that includes a panel, if you will, of the most common types of genes that have thus far been associated with various genetic forms of epilepsy. So a DNA panel will include, whether it’s 50 or 100, or 50 or 500 genes in which there is evidence that there is an association with epilepsy, and it will test specifically for those genes. On the other end of the spectrum is called, is something called whole exome sequencing. Now, if I use the term whole genome sequencing, I think most of you would probably appreciate that that means that the process involves sequencing our entire genome. The three billion base pairs of our genome. But it turns out that only a very small percentage of our genome actually encodes proteins themselves. And that part of the genome that encodes proteins is called an exome.

So whole exome sequencing is much less costly and much more efficient. And so we’re turning more and more to doing whole exome testing so that we have a chance to, I say, the entire exome of an individual rather than just being limited to the DNA panels or arrays. These are carried out by clinical testing labs all across the country and in the world now. And the main limitation at this point for people in which there is a reasonable chance that a genetic cause might be identified. The real challenge that we’re currently having at the moment is getting health insurance to cover the cost of that testing. You heard from Laura before that the epilepsy genetics initiative is a large national, international effort to try and collect as much of the data that is being produced in these clinical testing labs as well as research labs. So that we can deepen our understanding of the complexity of the exome and discover more and more epilepsy genes.

Can you speak briefly about some of the environmental factors that can actually modify genes?

Yeah, we have a fairly limited understanding of that to date. I think the most obvious environmental factor that we know can mutate DNA is actually sunlight. So we know that ultraviolet exposure and extreme sunlight can directly damage DNA and the evidence for that is that as we age, we have more and more of a predisposition for skin cancer. Especially any of us who have not taken a caution on using proper protection lotion throughout our life. So light itself is directly damaging. There’s also evidence, clear evidence of various toxins to be damaging to DNA, so called teratogens. And in some cases that’s even been associated with certain drugs. We know that a very significant number of environmental toxins associated with pesticides can be DNA damaging as well. But this is an area that I think has received relatively limited study to date. And my hope is that we’re going to make significant advances in the years ahead in that regard.

Can you just clarify again, some about how a child can inherit epilepsy from a parent and the parent be unaffected, even though it did come from them?

Yes. So in the most well understood case, the parents may be unaffected, but there may be other members of the family that are affected. So that goes back to the family tree that I showed before. So in that case, if the parent is carrying one copy of the gene that person won’t be affected. But if they happen to have a child with a partner who also carries that gene, then the child would receive both copies and be affected. So that’s the most straightforward case. But I think the questioner is asking what about if there’s not any epilepsy that’s evident in the family? And especially in the case where you can really trace the family tree on both sides. And that individual may be carrying a mutation that is not causing epilepsy. But the child, in fact, does then develop epilepsy.

We don’t completely understand this yet. But that gets back to the previous figure, where I showed that we believe that many, many cases in which there’s a genetic influence on the epilepsy is due to polygenic changes or small change, relatively small changes in the various proteins. But many proteins because a number of different genes are affected, so it’s not a single gene mutation. Of course, the other very important reason for a child developing epilepsy born today to both parents who don’t have any evidence of epilepsy is what I talked about before. And that’s this idea of de novo mutations. In other words, the mutation in the child was not inherited from the DNA from the parents, it appeared only in the sperm and the egg. And so this is not something that would be inherited. Now, that child now does carry that mutation. And if that child had children, depending on the mutation and severity, it could theoretically be passed on to the children of that particular child.

If EGI has a population of 700 plus participants, how many are needed to do an effective population level genetic analysis of epilepsy?

The vast majority of cases of people who have epilepsy, in which there’s a genetic, a primary genetic cause or genetic influence, have that epilepsy because of sometimes subtle mutations in many, many genes. The only way that we’re going to be able to figure this out is by doing a genetic analysis by doing sequencing, whole exome and whole genome sequencing on hundreds of thousands of people with particular, with epilepsy or whatever the disease type it is. We now are appreciating just how complex the genetics is in the majority of cases. And we now believe that it’s going to take certainly many, many, many tens of thousands of people. And ultimately I believe it’s going to be hundreds of thousands of people for us to really decipher this.

So EGI is a kind of approach that we need to have, where we bring together the different data-sets that are being produced all around the globe. Again, whether it’s from individual clinical testing labs or large research groups that are doing sequencing on hundreds of people or thousands of people. If we can work out the arrangement to be able to bring all that data into one common data set. I don’t have any question that we have the capacity for being able to do an analysis on hundreds of thousands of people from around the world, which is going to be the critical step for understanding the complexity of this type of genetic influence on epilepsy.

Does the genetic testing have to be done with just the person who has epilepsy, or does it have to include other family members’ DNA as well?

In many cases, it’s the ideal is to have the DNA from the affected person and both parents. But this is actually changing, in part because of the creation of larger and larger data sets. The statistical geneticists are working out approaches that allow a comparison between just a single individual and the increasingly large data sets that contain sequence from both affected. And in our case, epilepsy patients. And very, very large, quote, “normal population controls”. So at the moment, again, depending on the situation, the clinician ordering the test will prefer getting DNA from the affected person and both parents. But I think that this is changing and over time, just getting individual DNA will be sufficient.

What percentage of epilepsy cases do you expect that will be identified by whole exome sequencing in the future?

Well, that’s a tough one. It’s a fool’s errand to predict the future in this way. But, I mean, given that we believe that roughly two-thirds of all the epilepsies have some type of genetic influence. And, by the way, I should also say that we think that in some cases of so called acquired epilepsy, that you’re genetic makeup also helps determine your likelihood of developing epilepsy. For example, everyone probably appreciates that traumatic brain injury, such as what can occur in a terrible car accident can lead to epilepsy. And in that case, we believe that the main event is the fact that there’s been a direct injury to the brain. But there is evidence to suggest that that individual’s genetic makeup may make it more or less likely. Just depending on their, the nature of their DNA. So in those cases as well, I think that we’ll get to the point where whole exome sequencing will allow us to essentially define what the map is of variations in DNA or mutations, that are the determinants of a person’s disease.

And I’m not going to say that it’s going to necessarily be two-thirds of all patients with epilepsy, but I would think that conservatively that it’ll be 50%. And there will be a day when we’re going to have an entire map of our own DNA with the predictions of how various mutations might affect our likelihood of developing epilepsy. But more importantly by having that map, we will be able to come up with very specific precise approaches to therapy that are tailored to the specific genetic basis of that person’s epilepsy.

Is it more difficult to determine mutations in generalized ability given that the brain is firing neurons from all over?

We have not figured that out yet. I’ve had the good fortune of being involved in a very large study called Epi4K that has involved hundreds of scientists and study coordinators throughout the world, in which we’ve collected and sequenced many thousands of patients with various forms of epilepsy. And we actually have attempted to answer that very specific question of what’s the likelihood of finding a causative mutation in patients who have generalized epilepsies versus those with focal epilepsies. And somewhat to our surprise in our first main study, we were able to identify a larger number of causative mutations in the focal epilepsy. So that actually went against our hypothesis and I think what the questioner is asking. But I don’t think this chapter has come to a close yet. I think there’s a lot more research that needs to go into this. And I suspect that we’ll be making advances in identifying mutations in both cases.

Is it possible for an individual to have a known genetic mutation, but not actually have the disease?

Yes. So I alluded to this before, I didn’t emphasize it. But all of us are walking around with variations. There are mutations, there are differences in DNA from one another. And some of us have variants that really are quite different from the normal population. And yet for reasons sometimes that we do and sometimes don’t understand that variation does not lead to any significant abnormal structure or function of the protein. Or it may lead to an abnormal protein but nature has come up with some other ways of covering the deficit that might occur from that protein. And so we have our normal health. So yes, we’re filled with variations in our DNA that fortunately more often than not actually don’t cause disease.