Good morning. That's a really hard talk to follow. And as Tristan mentioned, I'm Krista Habella. I'm a pediatric epileptologist, and my name is spelled with a C-H. And this is Krista Schatz. She's a genetic counselor who works in our Epilepsy Genetics Clinic. Her name is spelled with a K. And neither of us has any conflicts to disclose. The learning objectives for today are to recognize two ways that current genetic testing recommendations may lead to dilemmas in clinical practice, to list two strategies for resolving of EUS, and to identify one to two potential dilemmas related to advances in genetic testing and therapy. Okay. Okay. So we were asked to discuss clinical dilemmas related to genetic testing. And if we had done this last year, this probably would have been quite different, because up until October 2022, last year, there were no formal recommendations in regards to genetic testing in epilepsy, which seems kind of crazy. But now, the National Society of Genetic Counselors Practice Guideline, which was endorsed by AES, recommends genetic testing for everyone with epilepsy, regardless of age. And the recommended testing is whole exome or whole genome sequencing as the first line test, and then reflexing to chromosome microarray. If for whatever reason, and there are many, whole exome or whole genome is not available, then it's recommended to start with a large multi-gene panel. And so we think this is a really positive first step. Hopefully, it will increase access to genetic testing for many people, but it also creates some challenges, don't you think? Yes, I agree. I think one of the biggest challenges, or two of the biggest challenges, are supporting the increased demand for genetic counseling and for figuring out how to interpret results, especially when we're talking about testing patients really early in their clinical course. When you get a new diagnosis very early on, it can still be hard to prognosticate, even though you have a diagnosis. One classic example that we see a lot in clinic is SCN1A. We have families in which a pathogenic variant can cause just self-limited febrile seizures that the patient outgrows, where other family members with the exact same pathogenic variant have a more classic Dravet syndrome presentation. And so then the question becomes, how do we counsel other family members when they want to get testing, either early on in their presentation or later, or even without having any symptoms? On top of this, making things even more complicated, we may be testing patients early and get a variant of unknown significance. And having a variant of unknown significance early on, we may not be able to exclude or include the US as pathogenic or not, because we're not quite sure what the full clinical presentation is. Yes. Okay. We will come back to the VUSs. I think we both agree that genetic testing early can be very helpful, particularly when it impacts management or for many of the reasons Tristan already discussed. It certainly can still be problematic when we are left with uncertainty, even after we get those clear, positive genetic test results. But let's touch on the increase in volume and demand for genetic counseling. So if you think about it, now one to three percent of the population qualifies for an exome or a genome. And there are about 6,700 genetic counselors in the US who are often the ones doing the pretest consent. And many of those genetic counselors don't even see patients with epilepsy. So how does this all get done? That's what I call job security for genetic counselors. Very true. But then also, maybe does this provide an opportunity for other providers to become more comfortable doing the pretest consent themselves? In addition to increasing availability of genetic testing, because more providers would be able to offer the test, it would allow for more genetic counseling, focusing on the counseling aspects once the results are in. I would agree 100% that we need to educate our neurologists and epileptologists to make genetic testing part of routine clinical practice. But time constraints became our problem here. Having the time to counsel patients on all of the possible epilepsy-related outcomes with genetic testing is simply not possible most of the time in a standard routine physician's visit, never mind having the time and the expertise to counsel on the secondary findings that we have to worry about with exome and genome. And pretest consent is really one of the most important parts of genetic testing, because genetic testing results are not straightforward. So explaining to patients things like a negative test result does not mean that there isn't a genetic etiology, or that a positive test result doesn't allow us to exactly predict the future. These concepts are really difficult, and if patients aren't counseled appropriately about them prior to testing, it can really affect interpretation of the results. And particularly for results in general, but when we talk about VUSs, there can be significant anxiety as a result, and then an overall negative experience. I see those points too. All right, so let's talk about the VUSs. They're the things that keep us all up at night, right? So we've all felt like this girl, right? As we all know, VUSs can be really common in genetic testing, and they're one of the most frustrating aspects of genetic testing for both providers, but also for families. It can be really difficult for many people, including providers who are not that familiar with genetic testing, to understand what a VUS is, let alone then try to interpret the relevance for the patient themselves. So when I'm pretest consenting for a family, I try to prepare them ahead of time by describing the different types of variants that can be found. I actually go through that there is a spectrum from pathogenic to VUS to benign, and I try to say something really concrete, like, yes, there is a change, a variant of uncertain significance, there is a difference there, but we don't actually know whether that change is disease-causing or if it's benign. You mean like Krista with a CH or Krista with a K? Yes. So there's a difference, but we don't know if it's a bad change. And it definitely confuses our patients. I would agree that VUSs are one of the most difficult things that we encounter in clinic, and it can be really hard to explain to patients that not all variants are disease-causing, and particularly when there are one or two variants in epilepsy-related genes, understandably patients want to get that diagnosis and see that that is, and believe that that might be the answer. Yes, but then it's also important for us to remember that most variants of uncertain significance ultimately will get reclassified as benign. It may take many years. So the data in cancer genetics shows that over 75% of VUSs end up being reclassified as likely benign, and the numbers seem to hold true in other areas of genetics as well, at least based on initial reports. Yeah, this is true. We don't want to over-diagnose, but the flip side of the coin is also true. You don't want to ignore a VUS because the phenotypic spectrums as well as the number of variants that are being determined to be truly pathogenic is expanding all of the time. Yes. And then we have to think about if a VUS by itself is not confusing enough, different laboratories may actually classify the variant differently. So one may call it likely pathogenic, and then another lab calls it a VUS. So what to do with that? There are specific variant classification guidelines, and it's shared in the resources if anyone wants to practice. They were published in 2015 by the American College of Medical Genetics. But studies have repeatedly shown that even with these very specific guidelines, there can be a lot of discordance in variant classification between different individuals. Yeah. And that really highlights the importance of clinical interpretation of VUSs, and that's really what we spent most of the time counseling patients on or working up in our clinic. Yes. So we spent a lot of time on that. So of the strategies that we use, what are some of the ones that you think are the most important to try to help reclassify a VUS? Yeah. I mean, so first of all, determining whether or not the patient's clinical manifestations match the phenotype associated with the potential pathogenic variant in that gene. But as I've probably already overemphasized, now that we're testing earlier, sometimes we may not be completely sure what the full extent of the clinical manifestations are. A lot of other VUS resolution strategies are related to specific genes or specific variants, but one of the most common things that we'll do is test parents or other family members. But it's really important here to understand that knowing the correct family member to test and what their phenotype, as well as the proposed mechanism of inheritance for that specific gene, is essential. There are also various different biochemical or metabolic or imaging tests that can be used to add information about the patient and about potential genetic changes. These, again, are specific to the gene, so a really common or classic example is when there's a VUS in the gene that causes GLUT1 deficiency. This needs to be resolved because there's potential treatment implications, and so we would typically recommend doing a lumbar puncture for CSF glucose if that hadn't already been done. In other situations, we may have a VUS in a gene that is related to epigenetic disorders. In this case, you can send out testing to look at known methylation profiles that might tell us whether or not there was a functional consequence of that VUS. But for all VUSs that we get, there's a lot of information published, and it's really important that labs should be doing this, but we should also be looking at that information with respect to our individual patients. And so things like what is known about the functional studies of that particular variant, as well as how prevalent that variant is in the general population, is important. A really important caveat here, though, is that most of the databases that we use here are generated from data that comes from predominantly Caucasian populations, and so this is important to take into account when we're considering our patients. Right. So if we have a VUS in a patient who's not Caucasian, and the variant is not in those population databases, it's important to consider maybe that variant is common in other populations, but it's just that that patient's heritage is not adequately represented in those databases. Yeah. So this is a huge area of disparity globally in the field of genetics. People are, you know, the field is working towards resolving this, but we're not quite there. Yes. Thankfully working, but lots of work to do. But so you brought up GLUT1 deficiency and lumbar puncture, and we had this exact situation with a family. So they did not initially want to pursue the lumbar puncture recommendation, even with the potential medical management implications. They did not want to put their baby through a lumbar puncture because thus far he was doing well on his current medications, and they also felt like they were confused because they had initially been told that this variant was unlikely to be the cause of his seizures. So couldn't they wait and see what happened? Yeah, this is really hard because the data says that most VUSs, or the majority, may turn out to be benign, but in this particular case, you don't want to miss a case of GLUT1 deficiency. So what ended up happening? After many hours with multiple different providers, they did end up pursuing the lumbar puncture, and his CSF to serum glucose ratio was low. So we told the family we considered the VUS to be likely pathogenic, and the neurologist recommended the ketogenic diet. So this is, you know, that's an example where it's fairly straightforward, but there's lots of cases where even if a VUS were to be determined to be a truly pathogenic variant, it might not have immediate treatment implications. And sometimes when patients are doing well, the families don't want to go through those extra tests. And so the question always becomes, why should we try to resolve a VUS, and when should we try to resolve a VUS? And that's not always a straightforward answer, and Tristan's given us a lot of good reasons why we want to resolve VUSs even outside of knowing that there's a definite treatment. But it's also important to recognize that genetics changes all the time, and the advances in clinical care based on genetic changes is one of the most exciting parts of being an epileptologist, but comes with challenges in its own right. Yes, so I feel like now with a positive genetic test result, one of the most common questions we get is, is there gene therapy available? And sometimes even families will find a trial and ask, is my child eligible? So I have a two-year-old with a pathogenic variant in SCN1A. He has focal seizures that started when he was around eight months, and they've been quite difficult to control since onset. So his family is completely focused on the potential for developmental decline, and his variant has been reported three other times that I could find in the literature, always associated with developmental and epileptic encephalopathy. But so far, he doesn't have any developmental issues. So what are your thoughts on this in clinic? How do you approach this? Yeah, so this is also a challenge. There are now various gene therapy trials that are related to specific diagnoses and are addressing specific gene-specific mechanisms. These are really exciting for patients and families who are candidates, but there are some more global dilemmas that they present. And so the biggest one is that when families are asking about risk versus benefit, we really don't have a lot of data about what the potential benefits or even what the potential risks are. And then on top of that, most of these trials are looking for patients that are young and newly diagnosed and have very severe epilepsy, and there may be age cutoffs. And when we're doing testing early on, and we're diagnosing patients early on, and the question about should they have gene therapy comes early on, we don't know how severe their epilepsy phenotype is gonna be. And so it's harder to establish that risk in the setting of unknown benefit. The other thing is that a lot of times we have patients that are getting their diagnosis late and there are age cutoffs for these. And so for our patients who we are seeing who are adults with epilepsy and we end up getting genetic diagnoses for them, which we're doing more frequently, as you mentioned, we get a lot of referrals for adults with epilepsy, because again, recommended for everyone with epilepsy at any age. So what are your thoughts for these older patients where maybe they don't qualify because of age? Yeah. So we definitely have a lot of patients that they may have developed their epilepsy in the classic infantile or childhood onset, but because of lack of technology or lack of access, they don't get their diagnosis until they're outside of any window for any gene therapy trials. But there are lots of genetic or gene specific or syndrome specific trials and treatments out there that they can still benefit from. And hopefully with increased access and the recommendation to test earlier, we will not have as many of those patients in the future. And then there are some genetic trials based on, for people with focal epilepsy. And focal epilepsy is another area with some fascinating updates in genetic testing. So if you were to do genetic testing in a patient with focal epilepsy on a peripheral sample like blood or saliva, the chance for genetic diagnosis is maybe around 8 to 10%, which even by genetic testing standards is pretty dismal. But if you have access to tissue, there have been some studies that show there's probably a significantly increased chance for a genetic diagnosis, particularly for people with focal cortical dysplasias or hemimegalencephaly. So how do you see this impacting clinical care? Yeah, I think this is a really exciting field, especially when you think about the surgery and how genetic diagnoses and surgical management of epilepsy interplay. So we know that, for instance, patients with somatic changes in genes associated with the mTOR pathway are much more likely to do better in surgery than those who have channelopathy, for instance. And so it potentially can be really helpful in thinking about surgical planning and other treatment options. But from what we know so far, the clinical course of action has already been taken because these people have already undergone surgery, right? Yeah. Most of the studies so far come from people who have already undergone surgery. But I would argue that getting the diagnosis is helpful in its own right. It can potentially help to guide future treatments. Even just having the diagnosis itself, as we've already heard, helps families for multiple reasons. But specifically, lots of people feel like they have to keep on looking for a diagnosis. And having the diagnosis may allow them to stop that. The other thing is that everything is advancing, technology, research, and there's research being done into pre-surgical somatic testing, and we may be dealing with those challenges in the future as well. And then that brings up the question, so what do we do for our patients when we've exhausted all the available appropriate genetic testing options and we still don't have a diagnosis? Research into polygenic genetic testing is promising, but it's not ready clinically for epilepsy. But it is already available in some other areas. Cancer genetics is already doing it. So we expect it to be coming soon. Yeah. And we likely need to start incorporating how to think about that in our clinical practice. And I'm sure we'll have many, many challenges associated with that. And I think that emphasizes that with all advances in clinical medicine come challenges. But I hope that some of the points that we've brought up help everyone to think and anticipate challenges that may come up, but also recognize how important doing the testing and continuing to look for those answers for our patients are. Yeah. And doing so requires careful considerations and certainly a team-based approach, which we do and we try to do. And importantly, including the family in that team. I think we have emphasized that early genetic testing can be really helpful, both for providers and families, can help provide medical management recommendations. Tristan emphasized all these different reasons that it's helpful for families, even if there's not a specific medication to use. And then also the opportunity to participate in research and clinical trials. All of these potential benefits can help outweigh the challenges that genetic testing can present, like the U.S. interpretation or potential uncertainty once you have results. And then, you know, a question I even address with families, after the genetic testing has been done, a lot of families share that even if there isn't an immediate impact on medical management or even if we don't get a genetic diagnosis, a lot of families are still happy and pleased that they went through the genetic testing process because the additional information they gained can be empowering.

genetic testing

epilepsy

whole exome sequencing

genetic counseling

variants of uncertain significance

gene therapy