Genetic Testing to Develop Personalized Medicine for Epilepsy

Wednesday, March 7, 2018
7:00 pm - 9:00 pm CST

This webinar recorded at Columbia University in New York City, focuses on “Genetic Testing to Develop Personalized Medicine in Epilepsy”. In this webinar, learn more about the importance of genetic testing in epilepsy, the different diagnoses you can receive from genetic testing, and what options are available after your testing results. Also, learn how CURE’s Signature Program, the Epilepsy Genetics Initiative or EGI, is helping push the precision medicine movement in epilepsy forward.

The webinar is presented by Dr. David Goldstein, Director of the Institute of Genomic Medicine at Columbia, and also features a Q&A portion. Some of the questions you might hear addressed include:

  • What is the value of genetic testing?
  • How do I go about getting testing ordered for me and/or my child?
  • What type of results can I expect if I do have genetic testing completed?
  • How can knowing the cause of my/my child’s epilepsy help with the available treatment options?
  • How is epilepsy research, like that involved in EGI, helping end the diagnostic odyssey that many patients face?

Plus, learn how genetic causes of epilepsy occur in this episode of our Seizing Life podcast.

Download Full Transcript

Audience Q&A with Dr. David Goldstein

Where can patients get information on clinical trials?

You can go to a government website which lists the clinical trials that are ongoing, And that is a comprehensive listing of ongoing clinical trials, meaning that when the compounds get in demand, they’ll be there. Trials that are being planned, but aren’t at the stage of being tested in people. It’s much harder to get a sense of what’s coming. And that’s actually one of the things that I think would be good to try to organize information around too to really try to figure out what’s coming down the pipe. But for things that are being tested one you go to that government website.

Are there any consequences of whole exome sequencing or any adverse situations that one would be aware of?

I think it is fair to say that, that there can be concerns in performing whole exome sequencing. One example is that it is possible that you would find out something depending on what’s done with the whole exome sequence data that would cause anxiety without providing a compensatory benefit. In most cases where this kind of sequencing is performed to explain an indication, for example, to explain a patient’s seizures. In most such cases the patient and care provider in fact will only find out about genetic variants in the individual’s genome that either are responsible for the indication or that are on a particular list of genes that have been highlighted by the American College of Medical Genetics as being important to communicate results back for.

And these so-called incidental findings are communicated back because they represent genes that cause presentations that are not only serious but whether it’s something that the individual can do about it. So, for example, on that list are genes that cause cancers where there are certain screening regimes that are recommended. Genes on that list include genes that cause heart arrhythmias where there are certain interventions that are possible, and where certain kinds of evaluations, lifestyle changes are important. So usually those are the only things that individuals will hear about.

But in some settings they might hear about other things for whatever reason once the data have been generated. And there are examples of things that one might find in one’s genome that could cause anxiety without clearly providing benefit. A very famous example of that is whether individuals carry a relatively common and very strongly acting risk factor for Alzheimer’s disease where there really isn’t anything that you can do about it. In most settings it’s possible to choose what you would hear about and not hear about. And so there you can make a personal choice about whether you want to know about these other things that are not related, for example, to the reason for the sequencing.

Can you explain why you’d want to have a patient and possibly their parents sequenced?

There are really two ways in which we use family members. One is really just to better diagnose the affected individual. And there it really does boil down to finding out what’s in the child, for example, that’s not in the parents. And that could be, as I already highlighted a so-called de nova mutation. So a variant that’s not in the parents at all, or it could be a genotype where the child has two mutation, one from mom and one from dad and mom and mom and dad have only one. And so this is so-called recessive gene. And we can actually then use the fact that it’s not present in two copies in either of the parents to help reassure us that it’s actually responsible for disease.

In other cases, we might test other family members to help us, for example rule out a possible cause in an affected individual. If for example, there was an affected person with an unaffected siblings, we might test a candidate variant in the unaffected siblings. And if it’s present too, we might say that we’re disinclined to believe that that variant is causing disease. And of course, when there are multiple affected members of a family, then we’re looking for genotypes that are in common across the multiple members. The only final thing I’ll say about this is that there are in genetics always wrinkles in stories and often you need to do careful testing to see whether there are any wrinkles. I’ll just highlight one that’s important.

The so-called de novo mutations. Those actually often start in the gene cells of the parents. So in either cells leading to eggs or sperm, and sometimes the mutations that are in those cells of the parents are in other cells too, but just not all cells of the parents. And in those situations, we actually can sometimes in fact look for maybe even modest effects in the parents or the possibility, even though it’s say an apparently brand new mutation of transmission to other children. And so there’s a whole bunch of different contexts in which we would look more broadly through families.

If a family has had a single gene testing done or even a panel of genes for epilepsy, when should they or should they go on and have whole exome sequencing? And then also in that same vein with new genes being discovered, how often should a patient actually undergo testing?

So, in terms of the first part, if the test was either a gene or indeed even a large epilepsy panel and was negative, it really is clear that, that individual should have whole exome testing because none of the panels are absolutely complete for genes that cause epilepsy. If however, a single gene test or a panel test identified a clear cut cause that when vetted by people that know their way around the genome well, and the identification of pathogenic variants really does look like the cause, then in fact it’s not really necessary to perform whole exome sequencing.

If you for example, had a suspicion of Dravet and you had the SCN1A gene sequence, then there was a protein truncating variant found there really wouldn’t be any reason to sequence the rest of the genome in that context. As far as how often you want to reanalyze, given new genes are being discovered all the time. Even though it is tapering off as I said, in comparison to where we’re at a couple of years ago, it still is the case that new genes are being discovered all the time.

And in fact we’re learning more about how to recognize mutations in the already known genes. So therefore, it really is better to reanalyze as often as you can. There’s of course, of course a cost associated with the analysis and interpretation, and so, it’s a question of how often is manageable. We came to the view that every six months was a reasonable compromise and trying to make sure that we didn’t wait too long. If there was a new gene discovered that would make a difference in an individual patient’s genome. But having the re-analysis be generally manageable. And I think that, that’s probably reasonable overall something like every six months or a year for re-analysis.

Where can people get information on the cost? How do patients generally pay for their whole exome sequencing?

Yeah. So let me just clarify to a distinction between the actual generation of the data and the re-analysis. So in general, you actually don’t need to redo the generation of the data or get a new test unless you’ve only had a panel, or a single gene tested.

With the exception that if the sequence data regenerated a long time ago, there’ll be lower quality. And in this context, a long time ago probably means around three plus years ago, maybe a little bit more than that. All the exome data generate after that is pretty high quality. So, it’d be a matter of re-analysis as opposed to retesting or regenerating the data. As far as the costs go, it’s really difficult to say much about what the costs really are because it’s impossible to get one’s head around how costing actually works in the clinical space because the advertised costs have nothing to do with the real costs or even what providers are actually paid. And I really don’t understand the reimbursement landscape well at all.

But what I can say is that the cost to actually generate the sequence data in the first place forgetting clinical economy environment this testing happens in, the cost to generate the data in the first place is actually pretty modest now. So, here at Columbia, the costs for us to generate a whole exome sequence data is 300 and something dollars per individual, and so the actual cost of the data generation. And then once you have a reasonable scale of ration, the marginal costs of the analysis per individual are not that high either, but of course in the clinical environments, a whole bunch of other costs that get included including the final interpretation by a board certified individual and whether a mutation actually causes a disease or not.

With the re-analysis being obviously taking care of a group through the EGI initiative, how do patients enroll in EGI?

Patients can enroll in EGI with the support of their care providers and the genetic counselors here at Columbia. And as far as the starting point for those that are at academic medical centers that are already partners in EGI, it’s a straightforward process to be enrolled. And there’s a listing at CURE Epilepsy’s website of those partners for those that are not already at an academic medical centers starting point to approach CURE. So, for those that are not at one of the already participating academic medical centers the starting point would be to reach out to CURE for a discussion about how best to enroll.

If you contact CURE Epilepsy. It’s 1-844-EGI-CURE or you can just email directly at So that it does get you in touch with the Columbia team and we can get you enrolled remotely, and actually from any part of the world.

Are there specific types of seizures identified with the information gained by genetic testing to date? And if so, is that an indication of who should be sequenced and who shouldn’t be?

In general, the answer is that it is the more severe and earlier onset epilepsies not specific seizure types, but really severity and age of onset where the genetic diagnostic yield is the highest. It’s not a zero in any of the so-called non acquired epilepsy. So when we sequence patients with more common forms of epilepsy such as genetic, generalized epilepsy, non-acquired focal epilepsy, we actually do still see apparently a contributing variants in a number of known epilepsy genes. And this is very strong statistical evidence that they do in fact contribute and if they’re not a sole causes. But if you consider those diagnoses, the diagnostic yield for those epilepsies is a much smaller proportion than the earlier onset, more severe epilepsy. So that’s where genetic testing is most strongly indicated.

There are a lot of genetic testing labs and diagnostic testing that are out there, are the known epilepsy genes, is that list, are they made available to those labs and are they aware of those new and current epilepsy genes?

I think that the labs actually do now a fairly good job of keeping up with the literature, a fairly good job when they interpret a patient’s exome. So I think in general, if there’s a mutation in a gene that is known in the scientific literature, most labs are going to catch that mutation and report on it. And as far as the lists go, the labs really do go to the scientific literature themselves and identify all of the genes that have been associated with epilepsy from the scientific literature. And now the scientific literature is relatively easy to interpret. There are some genes where when you actually look closely, you see that the strike revenues for them isn’t so strong in the literature but in most cases it’s relatively easy to interpret the literature.

Will there be a future in gene therapy with the database that you’ve collected?

Here at Columbia and I imagine other places, there are a wide range of views on that. My own personal view is that gene therapy in all of its various forms is something that we absolutely need to explore for serious neurological conditions including epilepsy. But I personally feel that in general, that’s going to be a pretty difficult path and that there’s not going to be a lot of effective gene therapies for epilepsies in the relatively near future. And I’m more optimistic of traditional pharmacological approaches that are targeted to the genetic cause. In the near term, and then gene therapy, just because it’s really hard. Whatever kind of gene therapy you’re talking about, to get the therapeutic agents to the right cells in the brain, it’s just a challenging thing to do.

Does EGI currently work with any pharmaceutical companies?

EGI currently doesn’t work directly with any of the pharmaceutical companies and above my pay grade to indicate whether or not we will. That sounds like Kate may want to say something about that, but what I can say is that there have been a number of conversations that a number of people have had with companies and I do think that there are a number of companies that are increasingly interested in seeing the development of an environment that will facilitate the kind of genetically targeted trials that I was describing earlier.

As far as future research with EGI and the data, is the database and how is it made available to the public?

The sequence data is available currently through (inaudible) I believe already. And so what that means is that you can apply to access the sequence data through (inaudible). And in addition the actual variants that we identified through our analyses are available on the webpage that I showed earlier. And the final thing I’d say is that EGI really is established on behalf of the broader community. And therefore, anyone who actually has suggestions of ideas of ways that the data in EGI should be analyzed, we are very receptive to discuss it.