Webinar: Genetic Testing in Epilepsy: Criteria for Adults and the Promise of New Treatments

Genetic testing has long been seen by medical professionals (doctors, insurance providers, etc.) as necessary only for pediatric epilepsy patients. Despite physician reticence to prescribe genetic testing for adults with epilepsy and access challenges, it is becoming increasingly apparent that genetic testing in certain adult epilepsy patients can be beneficial.

In our last webinar, viewers learned that genetic testing can shorten a patient’s diagnostic odyssey, help tailor specific treatment options to their type of epilepsy, and aid in family risk and planning decisions. Many of these benefits also are relevant to adults with epilepsy including those who developed epilepsy as children but at a time when genetic testing wasn’t as widely available. After viewing this webinar, attendees should be able to:

  1. Identify adult epilepsy patients who would benefit from clinical genetic testing.
  2. Understand the types of clinical genetic tests available and how to interpret them.
  3. Distinguish between clinical and research genetic testing and the value of being involved in research studies.

In addition to the information above, attendees will also hear from a person living with epilepsy who underwent genetic testing as an adult to learn more about their motivation, experience, and how it was beneficial to their overall health and well-being. This webinar is the second part of a two-part series in March that reflects CURE Epilepsy’s ongoing focus on epilepsy genetics and research on rare epilepsies. Attendees will receive a link to view part one in an email to follow this webinar.


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About the Speakers:

Gemma Carvill, PhD is an Assistant Professor in the Department of Neurology at Northwestern University in Chicago, IL. Her lab uses genomic technologies, machine learning and high-throughput functional assays to define the molecular basis of epilepsy, including coding and non-coding genetic variants. Her group also uses patient-derived stem cell models to study how rare variants in genes involved in epigenetic mechanisms cause epilepsy. Dr. Carvill co-directs the Adult Epilepsy Genetics Program at Northwestern Medicine with the goal of expanding neurogenetics research and facilitating genetic diagnoses for patients. She also works with colleagues in South Africa to develop strategies for increasing access to genetic testing, and building genetic epilepsy research in sub-Saharan Africa, to ensure that precision therapies benefit all individuals affected by epilepsy.

Elizabeth Gerard, MD is an Associate Professor in the Department of Neurology at Northwestern University in Chicago, IL.  She is an adult epileptologist with clinical and research interests in the care of women with epilepsy and genetic diagnosis in adult patients with epilepsy.  She also directs the Women with Epilepsy Program at Northwestern Medicine as well as the Adult Epilepsy Genetics Clinic.  Her research interests include gene discovery and variant interpretation in adult patients with epilepsy. She also studies pregnancy and contraception in women with epilepsy and is the site-PI of the MONEAD (maternal outcomes and neurodevelopmental effects of anti-epileptic drugs) study. Finally, she is interested in the use and understanding of continuous EEG monitoring in the critically ill and is the site-PI for the Critical Care EEG Consortium.

Q&A with Dr. Elizabeth Gerard and Dr. Gemma Carvill

Will genetic testing tell you if your type of epilepsy could be passed down if you have children or if it won’t be?

Oh, thank you. That’s a great question. And I want to say that the way I got into this space in the first place was that I was counseling patients about pregnancy, which is how I started my career. And I felt like I knew everything that they wanted to know about the seizure medications and about epilepsy, and that in most cases, pregnancies are very successful. And I realized pretty early on that I wasn’t answering all of my patients’ questions because so many patients have the questions about heritability. And that’s actually how I started working with Lisa Kinsley, our genetic counselor, and this clinic grew out of that. I will say, and this is something that we want to study, we’ve been learning that answering that question for individuals is not as clear cut as it might seem, and I’ll kind of go through some of the reasons why the short.

So the first thing to know, is that if you don’t have genetic testing, depending on your epilepsy type, the chances of passing on epilepsy is not terribly high. We know that for studies of big populations of patients. That of course changes if you have many individuals in your family with epilepsy or you have specific types of epilepsy that are more likely to be genetic. So in those situations, we do recommend genetic testing to help you better understand what the cause of your epilepsy is and what the heritability of it is.

One of the reasons it’s tricky, and I want to compare and contrast this with, say for example, prenatal genetic testing you might do with an OB, is that our understanding of what’s called the penetrance of these disorders is slightly different. So we may have, in some cases we diagnose a genetic epilepsy that’s associated with a single gene and you have to have only one copy of that genetic change to be at risk for epilepsy. And those are the type of genetic changes that we often diagnose if we are diagnosing a genetic condition, and those pass to each individual 50% of the time.

However, just inheriting the variant or the genetic change doesn’t necessarily mean the individual will develop epilepsy. So we get into this probability model where it’s like, “Yes, we made the genetic diagnosis, yes, you have a 50% chance of passing this on.” And again, this is rare, it doesn’t happen often, but the likelihood that your child who inherits it will develop epilepsy can be variable, can be 60% in some of the situations that we deal with.

And so yes, it helps. It helps to understand the inheritance pattern. It helps to understand your genetic diagnosis if you have one. Another example is you may find out that your epilepsy is due to a recessive condition, and if it’s due to a recessive condition where you inherited a genetic change from mom and dad, the chances of your passing it on are very low.

But we are learning that because there’s so much uncertainty in our results, including the variance of unknown significance, including the likelihood of genetic change causes a condition, that a lot of times it’s not black and white as it is in some other forms of sort of prenatal genetic testing. So that’s why that if you’re doing genetic testing with the thought process of, “What’s the risk to my child going to be?”, that you do this very carefully with a genetic counselor and someone who understands how to explain this. And this is where I think it’s really important that your perspective partner also come to the visit as well.

Is there a way to use the Northwestern team for genetic testing if we are in another state?

Take that one, too. So, we’re very excited and we’re hoping to expand this. We do a lot of our consultations virtually now. We also do some in-person. And it’s not just me, I’m really happy to say that Dr. Scott Adney has joined me and we have other people who are hopefully going to join our team as well. I’m licensed in a few states, but not all. And if you’re not in a state where I’m licensed, then you can travel to Chicago if you’re willing to come and see us.

I will also say that interest in this type of specialized clinic is growing and there are several others throughout the country. I just want to highlight some of my colleagues at University of Pennsylvania, University of Alabama and Stanford are some of the people I work with. So if you’re in one of those regions, I’m sure there are more developing, but these are people I know and work with who are doing something very similar to us.

Would genetic testing help determine which medications will help?

So in the psychiatry space and sometimes in the neurology space, there are tests which tell people how you’re going to metabolize drugs. I think it’s important to understand that that’s different than what we’re talking about here today.

Yes, sometimes if we make a specific diagnosis of a genetic condition, there already are specific treatments, including the ketogenic diet or specific medications that you should try or not try based on your genetic diagnosis. Dr. Carvill also talked about that we’re more and more gene therapies that are developing, but in many cases, making a diagnosis does not yet lead to an immediate treatment, just like Maggie spoke about. It’s more the hope for the future.

Would genetic testing help with diagnosis with somebody with generalized seizures? And what type of genetic testing should they start with?

Do you want to try that? Still me? Okay. Actually, I don’t know if we can share or if you want, but I had in the extra slides, the sort of algorithm that’s recommended by the Genetic Counseling Society to go through testing in general. As I said, that the genetic generalized epilepsy, so I want to first make a distinction. Many patients have generalized seizures, so generalized seizures can occur in a bunch of different disorders. Sometimes we refer to the term generalized seizures just because you have a convulsion. So I don’t want to presume that having generalized seizures means generalized epilepsy. Generalized seizures occur in all genetic conditions as well. So, generalized seizures certainly don’t preclude testing.

Having what we often call a genetic generalized epilepsy or idiopathic generalized epilepsy, some of the examples of that might be, for example, juvenile myoclonic epilepsy. It’s a combination of having epilepsy usually with convulsions and certain features on your EEG, usually without developmental delays. That particular group of patients has a lower chance of having a positive result on genetic testing right now with what we have available. Doesn’t mean you shouldn’t do it, I think that’s a nuanced discussion we have with our patients, but I would put that way under 5% of getting a positive result.

Which test to do first, I think depends. So the Society of Genetic Counselors recommend for all epilepsy genetic testing now, to ideally start with either an epilepsy gene panel or an exome or genome test. That may be hard cell for the idiopathic or genetic generalized epilepsies. I also would mention that a microarray, which looks for deletions and duplications, like Maggie was describing, if you’re really questing for an answer, I’ve actually found that test to be useful in the generalized epilepsies. Again, with the implications of the results being somewhat variable

This one is related to Ring 20, and it’s recognized that it’s very rare, and in this case it’s a somatic mosaicism. Is anybody researching this specific type of epilepsy?

So, I’ll make one point while Gemma thinks about that, but I’m ultimately going to toss it to her. One point about the ring chromosomes, as I mentioned that if your testing is negative, make sure that every stone has been unturned. Ring chromosomes are extremely rare disorders, can happen in multiple different chromosomes. And there are societies for several of the ring chromosomes disorders, but that is one of the diagnoses that would not be picked up with our big test, with our exome or genome. You actually have to do a very old test called a karyotype to diagnose ring chromosome.

And Lisa and I are unfortunately finding that less and less companies are offering that because it’s not been offered as much. So we’re actually trying to make that diagnosis on a patient right now. So it’s just an interesting point, that a karyotype is the only way to diagnose ring chromosome. As to specific, we are not doing work that I know of at Northwestern on ring chromosome disorders, but there is definitely research and groups working on it. And I was now waiting for Gemma to come up with who they are.


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.

Webinar: Genetic Testing in Epilepsy: Understanding Results and Their Impact on Care

Genetic testing has increased our understanding of the genetic causes of epilepsy exponentially in the past two decades, specifically helping researchers identify many genes responsible for rare childhood epilepsies. Recent studies found that in addition to providing patients and their loved ones some relief in ending their often too long diagnostic odyssey, genetic testing can enable tailored treatment options and can help with long-term outcome prediction, and family risk and planning decisions. However, there are still many individuals who lack a genetic diagnosis, including adults who may not even be aware that they could benefit from genetic testing.

This webinar will help viewers understand who may want to discuss genetic testing with their doctor and then will explore the following topics following genetic testing:

  • How to read a genetic testing report.
  • What are the different types of genetic results (or variants)?
  • What are the differences between benign, pathogenic, and uncertain variants?
  • What to do after receiving a genetic diagnosis.
  • How do these results impact an epilepsy treatment plan moving forward?

This webinar is the first of two webinars in March that address CURE Epilepsy’s ongoing focus on epilepsy genetics and research in the rare epilepsies. Our second webinar will be presented by Drs. Gemma Carvill, PhD and Elizabeth Gerard, MD from Northwestern University focus on genetic testing in adults and will be held on March 22, 2024.

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About the Speakers:

Katie Angione, MS, CGC, is a neurology genetic counselor at Children’s Hospital Colorado (CHCO) in Aurora, Colorado. She provides genetic counseling for a diverse population of patients with complex neurological disorders, with a focus on developmental and epileptic encephalopathies. Katie works with patients and families with rare diseases in CHCO’s Rett Clinic, Neurogenetics Clinic, and a multidisciplinary clinic serving patients with STXBP1, SLC6A1, Ring 14, and Chromosome 8p disorders. Her primary goal as a genetic counselor is to support patients and their families through education, advocacy, and research efforts focused on understanding the natural history of these conditions, and eventually working toward precision diagnoses and treatments. 

Q&A with Katie Angione, MS, CGC

One is, this person was informed that the gene that’s been identified for Doose Syndrome has been found but not for JME. Is this the case, do you know?

So I know that Doose Syndrome or EMAS has a couple of different terms for it. It’s something that we’ve been trying for years to find the gene and there are definitely some genes that have been associated with it. There’s still multiple
different genes that can cause that presentation. Doose is a clinical presentation and so there’s not one gene, one clinical diagnosis, there is a little bit more complicated than that. JME, I know that there are some gene associations. I’m not sure off the top of my head what they are. There’s so many genes at this point to keep track of. But again, I think there’s a lot of patients who have a JME presentation who we’re not able to find a genetic cause for. So that might mean there is a genetic cause, but we don’t know the full list of genes that could cause that type of presentation yet.

What about roadblocks to insurance paying for genetic testing? Do you have any recommendations for families who face that issue?

Yeah, that can be really tricky and my experience has been that insurance providers are always changing their policies. I would say that if you work with a provider who’s comfortable with ordering genetic testing, they might be able to go to bat for you a little bit. So we often will write letters of medical necessity. A lot of our physicians will have peer-to-peer discussions with insurance companies to explain the reasoning behind doing testing. But it might be helpful if you’re seeing that testing as getting denied, you might be able to request a copy of their policy and some, sorry, I’m losing my voice, some insurance providers actually cover very limited genetic testing, so maybe single gene or a very small panel or microarray. And then very extensive genetic testing, like whole exome sequencing, but they might not cover a lot of the panels that we typically send in between.

So that’s something we struggle with a lot is wanting to send something more targeted, but then only having the option to send something really comprehensive like whole exome sequencing. So I would say have that discussion with your provider that you’re talking with about genetic testing, about what those options are and if there’s something that would make sense to send that would fit within that insurance provider’s policy. There’s also some genetic testing labs that have pretty good self-pay options and patient assistance programs. So some of the labs that we work with commonly, Gene DX and Invitae, Prevention Genetics, worked with [inaudible 00:42:31] over time depends on the tests we’re wanting to send, but a lot of those commercial labs do have really good programs for self-pay options. So that’s something else to consider. I know sometimes going through a hospital system can lead to higher costs, but going directly to the lab might be more feasible. So that’s something to look into.

I know that there have been some free testing programs. Is that still the case for our community?

Yes. So I work in neurology and with epilepsy, so that’s my bias here. Those are the things I’m most familiar with. But Invitae does have a program called Behind the Seizure that is sponsored by a bunch of different pharmaceutical companies that are working on or that have treatments for some of the genes on that panel. So that is an option for children who have epilepsy that are under the age of eight would have access to that program. I know Invitae also has a long list of other sponsored programs that is always changing over time, so I’m not sure exactly what’s on that list right now. And then Prevention Genetics definitely also has some sponsored testing options as well. I would say that that’s another thing that family groups and patient advocacy groups are good at informing their community about. So that might be a place to turn if you’re looking for a sponsored test that would work for you or for your child..

Would you recommend siblings get genetic testing?

So it depends. So if there is say a diagnosis of a rare disease in a child and their siblings are also children, so they’re under the age of 18 and they’re not expressing any symptoms of that disease, we don’t typically recommend what’s called asymptomatic or predictive testing for siblings until they’re old enough to participate in that conversation. So that doesn’t necessarily mean 18. We definitely have those conversations with teens depending on exactly what the disorder is and what their level of understanding is. But in general, we try to avoid testing minors unless there is a specific treatment or something that could really impact the course of the disease. So if a sibling, for example, is diagnosed with CLN2 disease, which is a genetic disorder that does have a gene specific treatment, we might test a newborn sibling to see if they have that same disorder because we know that it can be helpful to treat very early on and can see potentially better outcomes when treatment is started earlier. So that would be the exception to that, is if there are potential treatment implications..

If children develop epilepsies, but there’s no known history for at least two generations, is there a benefit for the parents to get tested?

I do think it is still potentially beneficial for parents to get tested. So if a diagnosis is made in a child and there’s no family history. It depends on the specific gene, but there are some disorders where someone might actually carry a mutation but not have any apparent symptoms. So that could be helpful for knowing about potential recurrence risks. I would say tuberous sclerosis is a pretty decent example of that. It has a very wide range of severity. So we sometimes see patients in clinic who have that diagnosis, they have the genetic diagnosis, there’s no apparent family history, but then we test parents and one of the parents has the same change. So for things like that where there is a wide range of presentation, I think it can be helpful if you want to know for sure.

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.

A Diagnostic Odyssey: Early Genetic Testing in Epilepsy

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

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Audience Q&A with Dr. Porter and Ms. Nye

We had one question that asked, ‘I am 66 and I’ve had epilepsy since I was 13. Is genetic testing important at my age? I have children age 31 and 28 who do not have epilepsy.’

Yeah. I think there’s a lot of detail that would have, to be fair, to have to determine if genetic testing would be helpful in this situation. I guess I don’t really feel confident in coming out strongly one way or the other, but I will say that genetic epilepsies are complicated. Mrs. Nye had the situation where her husband and her both have mutations in this particular gene and they’re completely healthy, and it was only when they came together that they had a child who had mutations in both copies of the gene. There’s other situations where a single mutation is new de novo in the child, and that won’t be passed on necessarily to the next child from the parents. I don’t feel very comfortable in saying that, but it’s something you can certainly talk to your epileptologist about.

What does Dr. Porter see as the major barriers to genetic testing in epilepsy?

Sometimes cost is as an issue. We have sometimes difficulty getting insurance to cover it or to cover all the testing costs, but many of the companies, including Invitae, but other ones as well are making the testing quite reasonable, meaning that there are programs for patients that are on Medicaid to help them fund the testing. Some of the companies have like a cutoff where you can’t be required to pay more than a certain amount for testing. That’s number one. I would say number two is sometimes interpreting the results. There, I’m very lucky cause I have a lot of genetics colleagues. I have a genetic counselor for just this situation, but we do come down to sometimes being not absolutely sure that the differences in the genetic testing are really causal.

I don’t think that that should deter you from testing because I think, as time goes on, it’ll become more clear whether differences are in fact causal, but costs and interpretation, I think, are still two issues that we face. The final thing though, is that there are patients that I know, I absolutely, in my heart, know have genetic epilepsy and we still cannot find a mutation. That’s why the EGI program is in existence, because if your exome sequencing, meaning the parts of the gene that make proteins don’t have a finding in them, the data can be uploaded to EGI, and it will continually be investigated.

I think in the future, some changes in certain genes that we don’t know right now cause epilepsy will be identified as causing epilepsy. So, it’s important to not think of this as a static question. Your gene testing is negative. Well, it’s negative at this moment. It doesn’t mean it’s going to be negative in a year or two.

Are there any consensus statements or practice guidelines that can be used to help support the need for early genetic testing in epilepsy when working with insurance or institutional send out labs?

Yes. I don’t know who sent that, but if you want to send me an email, I can send you a generic version of a letter that we use. I think the Lennox-Gastaut Syndrome also has some generic wording on some letters. I will not say that they’re always successful, but I think it’s a worthy cause, so it’s worth trying to do that. Feel free to just send me an email and I’ll give you our generic a letter. But again, some of the companies now have very low copays, or even an amount that you don’t have to pay over if the insurance refuses to pay for it. I think there’s ways to work around the insurance companies, to some extent, but I do have some generic letters I could send you.

If I don’t have many genetic colleagues at my institution, can I ask for guidance and testing and interpretation from the genetic testing lab?

Yes. They all have genetic counselors, at least when you say that. I’m almost positive they all have genetic counselors, at least in my experience they do. They can walk you through some of the interpretations. If that’s not fruitful, I think referring to some of the epilepsy genetics clinics that have been kind of springing up around the country, or to somebody that has more expertise in epilepsy genetics would be another reasonable option, even if it’s not at your institution. Sometimes families are willing to travel for something so important.

Do you recommend biochemical testing for metabolic disorders prior to genetic testing for epilepsy or should these be done simultaneously?

Yeah. We’ve spent a lot of time working up a protocol that we’re instituting here on how to work up a child, in this case, with suspected genetic epilepsy, including metabolic epilepsies. We have decided to kind of take a multi-pronged approach. So, we do metabolic testing, often simultaneous with the genetic testing. I would say there are certain circumstances where we might vary that slightly. It also depends a little bit on the patient’s situation. So, if it’s a very severe catastrophic epilepsy and they have features that make us highly suspect metabolic diseases, then we would definitely push for that more strongly. If the epilepsy seems to not be as severe or we think, it’s much more likely, it falls into a certain genetic syndrome, then we might skip the metabolic testing. But right now, our pathway is to do them simultaneously.

How do you broach the topic of genetic testing with a patient given that their diagnostic odyssey might already be expensive?

At our institution, MRIs are extremely expensive, especially if there’s a need for sedation. I think we just need to get our head around the fact that we don’t blink too much at the expense for that MRI, and our genetic testing is about a 10th of that. So, I agree medicine’s very expensive, but the yield from genetic testing is quite a bit higher frequently than an MRI, and I don’t really worry about the $10,000, $20,000 MRI. So, doing an exome sequencing seems like a bargain to me.

How early is too early for genetic testing in epilepsy?

If they were going to go forth and multiply again, I would guess maybe they would do testing in utero, now that they know what they’re looking for. If you don’t have a clear cut epilepsy gene that you’re looking for in a pregnancy, I don’t know that I would test the baby. That’s probably not reasonable in utero. We send genetic testing on neonates a couple of days old if we think they have a neonatal epilepsy.

Do you think it makes more sense to start with an epilepsy panel or whole exome sequencing?

So we still use epilepsy panels before we do exome. I don’t know when the tipping point is going to come when we stop doing epilepsy panels and we flip over to just doing exome, or then, now some of my patients get a whole genome if the exome has been negative. I guess for right now, anyway, I usually start with a panel because the yield is pretty high in many of my patients. But some of them that are negative, we do go on to do exome, or as I said, rarely now we’re doing whole genome.

How did you know which steps to take, to establish your foundation and work towards discovering treatment for your children’s condition?

I was really lucky to have friends that I had met along the way who also were dealing with rare diseases or had started foundations of their own. I was actually hesitant to do it. We tried triheptanoin first. We thought there was a treatment out there, and so we’ve tried the treatment before we started the foundation. It was only when it became clear that the gut instincts of treatments weren’t working that we decided to take a step back and formalize and organize everything. We continue to be close partners with other organizations. There’s a lot work to do. We certainly still work with CURE Epilepsy and other organizations that are also fighting the epilepsy battle. But I think it does just depend if you have enough patients and if there seems to be enough information to gather and enough work to do.

This is Brenda. I would just say that, of my families that I give them a diagnosis, I tell them to go out there and look. There’s almost always a Facebook page or some other group that they can meet with and start to talk about what their children have or how they’ve dealt with certain situations. So, getting together with other families that are sharing all the things that you’re going through is really important. Mrs. Nye is amazing, because she has taken it an extra step and raised money to really work on epilepsy that her children have, but even just getting together with other families is so helpful. It’s helpful to me sometimes in taking care of the kids, because the parents will say, “Oh, we talked to this family in Brazil and they tried this and it seemed to help their child. Can we talk about that?” That’s something I might not have known had they not been in contact with another family?

How do you know which epilepsy center is the best, and how do you find the best neurologist for your child near your home? How did you come to seek out epileptologists around the world?

I guess we tried to find the neurologist that had maybe seen something similar to what we thought we were dealing with. It might not be the same doctor or the same place for every family, but I tried to get an idea of what neurologists or epileptologists or geneticists might have seen something like this before.

I think seeing large numbers of patients with epilepsy and genetic epilepsies is very helpful. You start to see patterns. I can almost always pick up a kid now. Well, I shouldn’t say this, but usually I can pick up a kid with a glucose transporter, because I’ve seen enough of them over the years, fairly successfully. I think it’s a little bit just seen a lot of kids with genetic epilepsies that allows you to see patterns. People who specialize in epilepsy as opposed to some general neurologist who see some epilepsy, but maybe specialize in headache, they may not be the right person to take care of a child with really complicated epilepsy.

We would see a great doctor, that doctor would maybe have three or four ideas. We would try those three or four ideas, and then maybe it was time to seek out another opinion to see if anybody else had the next three or four ideas. As a parent, you don’t really have the option of giving up, so you just keep going and keep talking and trying to find a doctor who has an idea that hopefully moves the child’s health in the right direction.

I think also the idea that in some places there may not be a lot of specialists, but if your physician is willing to work with somebody else that’s more at a distance, that that’s always very reassuring. I certainly have people that I think of as colleagues around California, for example, or Hawaii I talk to about patients. They’ll send me some information and I’ll try to assist them as best I can. Even if your local physician may not be the world’s expert in X disease, they can certainly reach out to someone who is, and it is a collaborative environment for the most part.

How do you find support from other families if you don’t know your child’s genetic diagnosis?

I would say that there are both broad and specific diagnoses. While we went on a 10 year odyssey to find the genetic marker for the type of epilepsy that the two of my kids have, we had other diagnoses along the way. Epilepsy, in and of itself, is something of a diagnosis. So, there are certainly support groups for other families dealing with epilepsy. We seem to collect different labels. As the years went on, things like CP or ataxia or apraxia, or just developmental delay. There are support groups for all of those more clinical descriptions of what’s going on. I think families do find some comfort in those groups as well.

There are, that I know of, support groups for infantile spasms, Lennox-Gastaut Syndrome. These are all seizure types, or seizure syndromes, and all of those organizations have networks. The Lennox-Gastaut Syndrome foundation is having a meeting in Orlando next month that I’m going to. If you find the type of seizure your child has, often they’ll be a group. Then locally, the epilepsy foundation of America has local chapters all over. For instance, the one in Northern California has a very … well, I think most of them around the country have the very nice camp for kids that gives them a sense of inclusion. They have a parent support groups they help with as well.

If there’s a family history of a genetic epilepsy and another child is born with the same genetic condition, would you start antiepileptic medication before seizures begin, or do you need to wait for symptoms to become apparent?

We do not have epilepsy prevention therapies. I work on a trial right now trying to look at that in tuberous sclerosis, whether we can actually prevent the development of epilepsy and autism in children with tuberous sclerosis, treating them before they develop seizures. But for the most part, right now, we don’t have therapies focused on the prevention of epilepsy. I personally, if I know that a child is at high risk for epilepsy, I often use EEG to try to make sure I’m not missing any seizures that are subtle, or just present on the EEG, but that is a conversation you would need to have with your physician to determine whether your child would benefit from frequent EEGs.

This is also important to note that some genetic predisposition to epilepsy does not absolutely say that child will have epilepsy. There are certain mutations that it’s highly likely they will have epilepsy, and there are certain mutations where some small percentage of patients have epilepsy and others don’t. So, it really depends on the specific situation.

Do you think that technologies such as antisense oligonucleotide therapies and gene therapy using the new vectors provide hope for various types of genetic epilepsies, or will these type of advances take many more years?

They definitely provide hope. I think that the timing of when these kind of therapies will be available is much more challenging. The neuromuscular field is obviously ahead of us as far as getting across the finish line with antisense or vector-based approaches for gene therapy. I don’t think epilepsy is that far behind, but it is a little bit more complicated in some situations about how to get the protein and all the cells in the brain, how to get it early enough. There are a lot of challenges, I think it’s coming and it probably isn’t fast enough for anybody that’s on the phone with a child with epilepsy, but I don’t know when, but just take heart that it’s coming. I just don’t know when.

What would you say to a mom who’s just beginning the diagnostic odyssey for their child with epilepsy?

I would say that there’s going to be some good days and an awful lot of bad days where you want to just give up, but I just take a step back, take a deep breath, and then when I’m ready to go at it again, you just keep trying. I think that you can’t just make the diagnostic odyssey the whole goal. A diagnosis helps certain parts, but it doesn’t actually change your child. Your child is the same child the day before you receive a diagnosis, as he or she is the day after. Even though continuing this research and finding a diagnosis are really important to me, and I think they are to a lot of parents and families, the majority of my time is still spent doing physical therapies and occupational therapies and figuring out IEPs at schools, and just trying to make sure my kids have hobbies that give them something to look forward to.

I think the diagnostic odyssey or a diagnosis in general is like a piece of the puzzle, but it’s not the whole puzzle. So, try not to just completely go down that rabbit hole, and try to have fun with your kid because you don’t get these days back.

What is the yield for a multi-gene panel and for exome sequencing for a patient with epilepsy? What would the yields be if the patient has additional features?

I’ve seen papers trying to address this question, and I think it’s extremely challenging because it all comes down to the denominator like what kind of patients you include in that group. I’ve seen 30% for a panel. Again, though, it really depends on the denominator. When did the patient develop epilepsy? What kind of epilepsy do they have? Do they have some other syndrome features? Syndromic features, meaning their ears are set differently, their eyes are set differently, their MRI has an abnormality on it that’s frequently associated with a certain genetic disease. I don’t know the specific answer, but I think it’s not 1%, and it’s probably not 100% percent. It’s probably somewhere less than 50%, but in the 10s to 20s to 30%, so good we’re doing, I think.

I just wanted to say that I liked Mrs. Nye’s description of ending on this that, understanding your child’s epilepsy is so important, but having fun with your child and doing things that you and your child both can enjoy is so important. The families that I see in clinic that really take that to heart and do things with their kids that their kids can enjoy, and that they can enjoy watching their kids enjoy is so important. Maybe your child’s not going to be able to play regular soccer. I had a patient last week that is playing in the special Olympics soccer team, and he absolutely loves it. He’s so happy with it, and his parents were really enjoying it too. That is so important, to taking care of a child with special needs, is finding out what they like to do and helping them do that. It just is a nice way to end, I think.

Doctor sits with little boy in the hospital bed, showing him information on a tablet.

Panels & Exomes: Diagnostic Yield & Detection of Childhood Epilepsy


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

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Audience Q&A with Dr. Swaroop and Dr. Sullivan 

Would you wait until the patient has had at least two seizures before considering genetic testing? Or would you consider genetic testing after a single seizure?

I think you really do need to wait for that second seizure, specifically in Dravet syndrome, we’re really trying to arrive at a very early diagnosis and we’ve actually looked to see if genetic testing should be sent after a young child under the age of one has had their first episode of prolonged convulsive status. That may be an isolated situation where I think a single seizure could be argued, but other than that, I think you really need to wait for that second seizure.

The table showed a relatively high yield of TPP1, can you speak to this?

Yeah, absolutely. And this was surprising to us as well and a couple of them were actually… It turned out a couple of them were actually because of signatures that are associated with TPP1 related Neuronal Ceroid Lipofuscinosis. So there was a prior probability that we would discover it. But in several of those other ones, we actually didn’t expect those. And so it may be that as rare as this disorder is, and perhaps it is under diagnosed. And some of you may know that there’s a program that BioMarin has that is looking at these individuals with mutations in TPP1 and seeing who may be eligible for a drug therapy. And I think it appears that this disorder may not be as rare as we’ve thought before. But really, I mean, even in the quarter of 2000 children we’re seeing a number but I would really be interested in seeing a much larger cohort and seeing if this number really holds true.

How difficult has it been for you to get genetic testing approved for your patients with epilepsy?

It really does depend on the type of insurance coverage. But it also depends on the attitude of the person on the other end of the line when you’re calling in to get the prior authorization. I would say that in my practice, because we still serve about 50% of our patient population is state-insured or under-insured, Medicaid Medical, that it is still very challenging, but I know that there are a lot of companies that are working with us to try and come up with an arrangement so that those patients who could benefit the most can get testing but that’s a process in evolution right now.

Is it best to order a panel that includes deletion duplication studies performed simultaneously with the sequencing? Or does it make more sense to see what the findings of the sequencing are and then only order deletion duplication for the genes indicated based on the sequencing results?

Yeah. I think that’s a good question for a couple of reasons. One, I think it’s fair to say that we really didn’t appreciate how prevalent these exonic copy number variants are in disease genes, aside from maybe a handful like Duchenne muscular dystrophy, or some of the other ones. But where we’re really seeing this evolve to is being able to detect a much broader spectrum of variants, including single nucleotide variants, indels, exonic, copy number variants, etc, all within a single test.

And so it should be, we should all be moving towards being able to get all those pieces of information together from a single test. And we’re finding through internal analysis of our data, that the prevalence and frequency of these exonic copy number variants is actually pretty high that it accounts for almost 10% of all the pathogenic variants that we’ve ever reported from Invitae. So it’s clearly a high proportion of clinically important findings. So my opinion, is that these tests should be looking at exonic copy number variants at the same time as sequence variants so we have the most optimal clinical sensitivity of testing.

When would you recommend testing an adult patient and is that something that you need to consider with a higher concern if they have relapsed? And what would your recommendations be for them?

I’m glad that this is being asked. I think that because I commented that a lot of the early onset epilepsies have a very high diagnostic yield, if an adult being seen in an adult epilepsy practice, had an infantile onset epilepsy, and there still is not a known cause, I would say that those group of patients actually represent a very rich group where the yield could be exceedingly high. Especially if the clinician has the time to go back and take that early childhood history, I’m convinced that there are hundreds of patients sitting in an adult epilepsy clinic with SCN1A mutations that had Dravet syndrome but then when they turned into adults they have a little bit more of a nondescript phenotype and our adult epilepsy colleagues may not have that index of suspicion. But I still think that those group of patients just to summarize, are those with infantile or childhood onset who continue to have seizures and have no known cause.

Webinar: Targeted Treatments for the Genetic Epilepsies – Clinical Cases

Plus, learn more about genetic forms of epilepsy in this episode of our Seizing Life podcast.

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Audience Q&A with Dr. Katie Angione and Dr. Lacey Smith

At what point in the diagnostic work up of patient with epilepsy would it be appropriate to order genetic testing? For instance, do you need to wait until the patient has failed at least two different anti-epileptic medications?

I think in most cases, it’s completely reasonable to order genetic testing pretty early on in the work up. Unless there’s a very clear structural cause on a brain MRI, genetic testing is reasonably high yield, especially if it’s very early onset, so infantile onset epilepsy. Because there’s the potential for identifying a treatable condition, I think it should be an important part of the work up.

As we kind of went over, a lot of the conditions, earlier you start treatment, the better the response and the better the developmental outcome. Then there’s also the potential for helping with medication selection. I don’t think that there’s really a need to wait until they failed medication and put the patients unnecessarily through that trial and error, because genetic testing can potentially give us some evidence to support a particular medication.

I’ll expand on that too and we talked a lot about treatment, but there are certainly other benefits for genetic testing and diagnosis outside of treatment, right? You don’t necessarily need to fail two epilepsy medications in order to start pursuing genetic testing. If families are interested in recurrence risk or are thinking about having additional children and wanting to figure out what the likelihood of having another child with this condition is, it can be part of the work up. As I mentioned earlier, it could reduce the number of tests that are warranted.

If you have a SLC2A1 variant, you may not need to do an LP for that for a small child. It could certainly reduce the number of tests during the diagnostic workup.

How do you know which epilepsy panel is best for your patients?

I think it depends on the patient obviously, which is often our answer. Sometimes a very specific phenotype or maybe you’ve done some biochemical testing, that may be pointing you in the direction of a certain gene or a class of gene. I think in those cases, it might make sense to start with a smaller panel, maybe even a single gene and then reflex to something larger if that’s negative. But for a lot of our patients, maybe even the majority, we don’t really have enough evidence to point us in any particular direction. There is a lot of phenotypic overlap in genetic epilepsy disorders. I think doing a slightly more comprehensive panel is, in most cases, going to be the best bang for your buck.

That way, you’re not extending the time it takes to reach that diagnosis. I would also say as far as which panel is best, which panel to order, there is a lot of options out there and that’s always changing. Labs are always expanding their panels, adding new panels, different options for rapid options. So, there’s really a lot to navigate. I think some of the important things to keep in mind are how big is the panel, what genes are included. If you do a bigger panel, maybe you’re increasing the chances of getting variants of uncertain significance which can be hard to navigate. But you’re going to be better at catching more rare disorders and maybe newer disorders, especially if the lab is kind of continually updating their panels as new genes are discovered. Then I think you also want to think about what is the coverage of the panel? What’s the minimum depth of coverage and the average depth of coverage? Because that’s telling you what’s the quality of that test? Are you going to miss something? Is there any chance of detecting higher level mosaicism?

Then the parental testing policies I think are something to be aware of as well because that’s going to help to resolve any variance. It might help to see if there is a recurrence risk, if it’s a recessive disorder, and then just overall how comfortable you are with the lab. Is there good communication? Is there a report that you’re able interpret well and feel comfortable sharing with families? A lot of things to take into account and I think it definitely depends on your specific institution and the patient population you’re seeing, but I think it’s something to look into and make sure you’re evaluating the panels that you’re ordering and asking questions of the lab, working with the lab to make sure you’re getting the best testing for yourself and for your patients.

Is deletion, duplication, and copy number detection important for genetic epilepsies or should that be left as a secondary option after sequencing?

I think it’s important to include deletion duplication at the onset. We typically order panels that include both sequencing and deletion duplication. I think that if you’re really doing a sequencing only panel, you’re missing the potential for a diagnosis there and just by doing it sequentially, you’re just expanding the time to a diagnosis for these patients.

I think I’ve definitely heard people kind of maybe arguing against deletion duplication and saying, “We don’t see a lot of evidence of deletion or duplications in a lot of these genes,” but I think honestly, we don’t really have enough data at this point to say that it’s not an important thing to do, especially for some of the more recently discovered genes.

Maybe we’ve only seen sequencing changes so far, but that doesn’t mean that there’s not the potential for deletion or duplication. As Lacey said, it would kind of be a shame to miss that by just doing sequencing and then have to go back just to make sure that you’re not missing anything.

Was the exome resequenced in order to find the PROSC gene? What changed in the analysis?

Affirmative. Sammy’s DNA wasn’t resequenced, but rather the lab just re-analyzed the sequencing data that was already available. I think it was a combination of factors. I think that the lab, in the time between the initial exome and the time that we got our re-analysis done, they may have changed their policy on reporting out candidate genes. Some labs are more proficient at reporting out candidate genes, so genes that really may not have been associated with any particular disease or disorder, but maybe it’s expressed in the brain, for example, and it’s a neurological phenotype. They may report those out with the caveat that it is a candidate gene and we know nothing about this, but just to keep this on your radar. As you saw shortly thereafter, we had the publication that came out. That’s helpful.

Doing a re-analysis of exome either on a clinical or research basis, the data’s there. It’s just our understanding of the genes. We have so many genes that we just don’t know what they do and what their involvement is in the human body, so our understanding changes over time. It’s not a change in technology, per se, in most cases. It’s really just our ability to interpret it and draw conclusions from that.

What can we do to keep drugs like ezogabine on the market so they’re available for patients? Is it a regulatory issue or an insurance coverage issue?

I think it’s different for different drugs that are available. Sometimes, for ezogabine, I think it was more of a financial issue. Ezogabine does have some side effects. Physicians were pretty reluctant to prescribe it, unless there was a pretty difficult to control epilepsy. I think for ezogabine, it was a situation where just not enough patients were on it for it to be marketable by the company, which is unfortunate but a reality. I think that really it’s been the families I’ve seen who have put in a lot of effort and advocacy and putting the information out there on how important this is and some labs and others are starting to catch on.

Are there foundations or patient groups that can help pay for enzyme replacement therapy?

I think there’s definitely a lot of advocacy groups out there. As far as how powerful they can be, that’s kind of another story. There’s so many rare diseases out there and all of these families are advocating for their children, their families, and there’s a lot to be overcome. I think it’s definitely a great thing to do to get involved with those programs. Honestly, the more people that do get involved, especially those that I think are in healthcare and are connected in a different way than the families, it’s certainly really helpful. Honestly, I don’t know the specifics but it goes a long way, just getting involved and even reaching out to advocacy groups, writing letters to politicians. Those things, they sound like they don’t make a big difference for something so rare, but you put enough doctors, enough families together doing those things and that’s our hope is that we can get to the point that we don’t have to deny a life-saving treatment because of insurance coverage.

Would specific EEG patterns, apart from hypsarrhythmia, give you an idea of which genetic etiology could be causing a person’s seizures?

There have been some cases that neurologists have come forward with a specific EEG pattern that’s directed very targeted treatments, so hypsarrhythmia as Katie mentioned, there’s the burst suppression in Ohtahara that I mentioned. We recently had a case, I don’t remember the exact EEG pattern but it was really suggestive of a POLG  related epilepsy so they were looking for that and there was a hit on POLG. So I think that there are some patterns but even when you do have a specific EEG pattern, so if you have hypsarrhythmia and you have spasms, there are a variety of underlying genetic causes of infantile spasms.

That may help the clinical diagnosis and give a general direction for genetic testing. There’s still, as Katie mentioned, so much overlap with the genes and the phenotypes for epilepsy. Yeah, very true. CDKL5, ARX can cause infantile spasms. I think there’s a list of maybe 15 or 20 different genes, so genetic testing definitely still is an important part of that work up, even if the EEG maybe points you in a certain direction.

Do you have studies on isodicentric 15Q?

I’m not aware of any off the top of my head, but that doesn’t mean that there aren’t available. I would say clinicaltrials.gov is usually my go-to for specific disorder targeted studies. Beyond that, I would say maybe one of the patient advocacy or support groups would be a good place to go. Honestly, Facebook groups a lot of the time can get you in touch with new research studies. Families are definitely very good at staying up to date on what’s going on and what studies are available.

Genetic Testing to Develop Personalized Medicine for Epilepsy

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.

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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, clinicaltrials.gov. 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 egicureepilepsy.org. 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.