Sharp Waves: ILAE's epilepsy podcast
Sharp Waves: ILAE's epilepsy podcast
Genetic testing: Variants of uncertain significance (VUS) - Dr. Gemma Carvill
What are variants of uncertain significance (VUS) in epilepsy genetic testing? How are they defined, and can those definitions change over time? Sharp Waves talks with Dr. Gemma Carvill as part of our genetic testing series.
RESOURCES
Standards for interpreting variants (American College of Medical Genetics)
EpiPred website for STXBP1 (developed by EpiMVP project - will be final by end of July)
Think Genetics paper – genetic testing in South Africa project
Link to Sharp Waves episode on genetic testing in LMICs
Sharp Waves episodes are meant for informational purposes only, and not as clinical or medical advice.
Let us know how we're doing: podcast@ilae.org.
The International League Against Epilepsy is the world's preeminent association of health professionals and scientists, working toward a world where no person's life is limited by epilepsy. Visit us on Facebook, Instagram, and LinkedIn.
Dr. Alina Ivaniuk: [00:00:00] Hello everyone. This is the new episode of the Sharp Waves podcast and I’m one of the hosts, Dr. Alina Ivaniuk. And today I have a very special topic which was widely requested and we think it's pretty relevant to everyday clinical practice, considering how widespread genetic testing has become.
Today we'll talk about the topic of variants of uncertain, some people say unknown, significance, and especially with this pertaining to seizure disorders and epilepsy. And today we have a very special guest to talk about this. With us today is Dr. Gemma Carvill. Dr. Carvill made her way from Cape Town in South Africa where she did her primary training all the way to the US, where now she serves as an associate professor in the Department of Neurology at Northwestern University in Chicago. She conducts vast research with a strong focus on understanding molecular [00:01:00] underpinnings of developmental and epileptic encephalopathies.
And more importantly, she closely works with clinicians at her institutions and helps them understand how the molecular biology of genetic variants interferes or intervenes with the clinical pictures that she they see, and helps them understand the clinical interpretation of genetic variants a bit better.
Today we'll be sharing her hands-on expertise and knowledge with us as it pertains to variants of uncertain significance. Dr. Carvill, welcome, we are very excited to have you.
Dr. Gemma Carvill: Thanks, Alina. It's great to be here to talk about one of my favorite topics. We like to joke in genetics that variants of uncertain significance are our job security, because there are always new variants of uncertain significance, and we are constantly working on lots of different ways to tackle these VUSs and resolve and give [00:02:00] answers to patients and families.
So I'm excited to be here.
Dr. Alina Ivaniuk: I think first things first, let's define what is a variant of uncertain significance. This is one of the several interpretations that we can see on genetic testing. Could you talk a bit more about what exactly means that the variant is of uncertain significance?
Dr. Gemma Carvill: Yeah, sure. So to kind of zoom out to doing a genetic test. What can you expect in terms of the results that you can get from a genetic test? And so of course, one option is that you perform a clinical genetic test in your patient or you yourself have had undergone clinical genetic testing. And one option is that there are no results.
But more often there is a variant that is identified and the variant can really come in three main classes. So the first class of variants, which are rarely if ever reported, are variants that are benign. And so these are variants that are present in an individual but have no impact in terms of causing disease.
And so they're called benign [00:03:00] or likely benign. On the other end of this spectrum, an individual can receive a pathogenic or a likely pathogenic variant. And in those instances, those variants are more than likely causative for a particular disorder.
And then we have variants of uncertain significance. These are the variants that sit in the middle of these two. So they're neither benign nor are they pathogenic, and they're of uncertain significance. And the reason that they are of uncertain significance is that we don't have enough information about that particular variant to call it one way or the other.
Variants of uncertain significance are the largest class of variants. I think the stat is almost 90% of genetic tests with genetic results that are delivered are these variants of uncertain significance. And it really just relates to the genome is a really big place and there are many, many variants. And while we've got really good at identifying genetic [00:04:00] variants, we're still developing new tools and understanding how a genetic variant can impact protein function and whether a variant is associated with disease, and so that's what a VUS is.
Dr. Alina Ivaniuk: Oh, yeah. So it's one of the possible options, and so far it seems that it's the most, the broadest field in which the result may fall into.
So we really need to know what that is and what it implies. What do laboratories do to determine the clinical significance of the variants? How do they derive this conclusion about the variant being pathogenic or benign or variant of uncertain significance? Could you talk a bit more about that?
Dr. Gemma Carvill: So there is now multiple complicated data matrices and kind of decision points that go into variant classification. And people have developed extensive tools and rules and guidelines around these. But to kind of [00:05:00] distill it down, all of these many, many rules and criteria, what it really comes down to is several different criteria that go into making that decision.
And so the first one is population data. We have now sequenced many, many individuals both with disease as well as with the general population. And we have a pretty food understanding of genetic variation in general. We can now use that information to assess the likelihood of a variant being disease causing or not.
For instance there are now multiple databases. Gnomad is a very popular one. And there is information from 800,000 individuals from the general population and the presence of genetic variants. The reason that that is important is if you identify a genetic variant in an individual with epilepsy in an epilepsy gene, for instance.
But we look at that variant, we ask, is that variant [00:06:00] present in the general population? And if it is at an appreciable frequency, then more than likely it is not causing the epilepsy in that individual because there are several individuals wandering around the world with that genetic variant and they do not have epilepsy.
This is especially true for the rare epilepsies, which is kind of primarily where most genetic testing is currently done, is really in the rare epilepsies. In general, those variants are not present in the general population. There are of course exceptions, which kind of leads me into the second criteria that we take into account when assessing whether a variant is pathogenic or benign.
And that's the mode of inheritance. There are different ways in which a genetic epilepsy can arise. They can either be recessive—this means that that it requires a genetic variant on both of the copies of that particular gene. Generally, a variant is inherited from one [00:07:00] parent, the mother say, and a second variant inherited from the father, and in the individual they need to inherit both of those pathogenic variants in order to manifest the disease.
Then there's also dominance. So this is where you only need to have one of the two alleles affected to manifest with the disorder. And there's de novo, which by and large account for the largest proportion of the rare epilepsies, and that's where that variant is not necessarily present in either parent, but arises de novo in the child. So technically not inherited. And so that information is taken into account when assessing pathogenicity. It varies from epilepsy gene to epilepsy gene. Some are dominant, some are recessive, and so that is taken into account.
For a recessive disorder, that variant can be present in the general population. Again, that's important because you need both copies to be affected. But they do still tend to be relatively rare in the population, so they're not present at high [00:08:00] frequencies because if they were, then it would be likely that individuals in the general population would have both alleles affected.
And so those are two of the main criteria that we take into account more and more, especially as research in this field is evolving. We're developing computational models and using things like machine learning and AI to really build these computational models that allow us to predict whether a certain variant is pathogenic or benign. We've used these in silico tools for many, many years, but they are becoming more and more sophisticated as we have more and more data. And there's more and more kind of protein structures and more and more research in this area. They're becoming more and more sophisticated, and that's a very active area of research that I'm happy to talk about.
And then the last kind of component that we take into account is functional data. For a subset of variants we now have functional data. This mostly pertains to things like missense variants where you switch out [00:09:00] one amino acid for the other, and those are super difficult to interpret because changing just that one amino acid in say the thousand amino acid protein is very difficult to interpret. More folks are kind of doing functional analyses in cells and in animal models to understand the effects of those variants. Collectively, all of these different avenues and pieces of information are put together to make a call about whether a variant is likely to be pathogenic or benign.
Dr. Alina Ivaniuk: Well, there are so many pieces to this puzzle. It's really a combination of some clinical things, plus computational models. There are some predictive algorithms. What should clinicians be aware of when they are sending out genetic testing?
Dr. Gemma Carvill: Yeah, so I think one of the major roles for the clinicians is that often when genetic testing companies receive a request for a specific genetic test, they can sometimes [00:10:00] receive minimal clinical genetic data. So often it's very minimal. So primarily “epilepsy of X onset” and sometimes additional neurological features. But a lot of that nuance is lost in the ordering of the test.
And so I think the major role that clinicians play, and we've seen this here at Northwestern as well, kind of in our adult epilepsy genetics program, is that integration of the clinical information is really important in allowing us to reclassify and classify variants. The clinician knows the patient best and the clinician has a good feeling for whether the clinical symptoms that have been previously associated with specific epilepsy genes, whether that's a good fit for the patient that they care for. And so I think that's a really a crucial role that clinicians play in terms of classifying and interpreting genetic variants.
And so for instance here at Northwestern we [00:11:00] work as a team on the kind of the genetics, genetic counseling and clinical side to put all of those pieces of information together to help interpret VUS. I think the other key kind of thinking beyond the clinician themselves, the thing about the clinical care team, I think another important fact factor is really, ideally, all genetic testing should be ordered in collaboration with a clinician and a genetic counselor. And so genetic counselors are really highly trained, highly skilled individuals who are trained in taking family history because that can also play a really big role in determining whether a variant is likely to be causative or not.
So for instance, I spoke about inheritance pattern, dominant, recessive. What is the family history? Is there a history of epilepsy or not? And that can change our interpretation as well. Genetic counselors are also key in making genetic testing accessible and understandable. I think genetics for many individuals, including many clinicians, was taught many, many [00:12:00] years ago, and in some instances wasn't even taught in medical school. And so I think that genetic counselors can be a very valuable resource for both clinicians and families in kind of understanding genetics and the role that plays in epilepsy.
Dr. Alina Ivaniuk: That sounds like clinicians play maybe one of the key roles then, if they are explaining, conveying that critical puzzle piece to the interpretation of the variant. I think that's probably one thing that everybody can take out. I will certainly take it out for myself, is to provide as clear and complete information about the phenotype as possible if I am submitting a request for genetic testing. And of course working with genetic counselors and genetic services in general to try to streamline those processes and make sure that the patient gets the correct testing and correct counseling. I think that's important things that you mentioned. That's great.
In the context of epilepsy, you mentioned a couple of [00:13:00] times different patterns of inheritance. Are there any nuances or any specifications specifically with regards to epilepsy that clinicians need to be aware of? Any differences with general neurogenetic things? I think there are lots of, not assumptions, but stereotypes about genetic meaning inherited. Whereas I think in epilepsy, especially with DEEs, we see lots of de novo stuff. Could you briefly talk about is there anything different from the other neurogenic disorders when it pertains to epilepsy?
Dr. Gemma Carvill: Yeah, so I think you hit the nail on the head that by and large what we understand right now, especially about the DEEs and in general, a lot of the rare epilepsies is that they do tend to be de novo in nature. A variant that is identified as de novo in a known epilepsy gene in an individual with epilepsy, almost 90, almost 100 percent of the time is going to be called pathogenic. So those are relatively easy to interpret. And I think that is an important part that in general, even if you don't see a [00:14:00] large family history, especially if it's early in childhood onset, you should still be thinking about genetics.
And I think that's something that our field as a whole has really struggled with for a little while. I feel like we're getting much better at that because we think genetic and we think, oh, there's no family history. It can't be genetic. But I think on the pediatric side, we have definitely gotten much better at that, about thinking about genetics in a child with new onset seizures that are refractory even in the absence of a family history. I think on the adult side, we're still getting a little bit better at that. And we're kind of learning from peds that in the instance of an unexplained refractory epilepsy to start thinking about genetic testing as well.
So I think that's one of the nuances. I think one of the other things in thinking about variant interpretation is also the type of variant. I think that is also very important. Most of what we understand about the rare [00:15:00] epilepsies is that most variants are loss of function. So anything like a truncating variant or a frameshift variant. What that does is it cuts the protein or the coding sequence short. And in general, that particular transcript doesn't make any protein. And so we call that a loss of function. And so those are really kind of red flag variants that they're more than likely going to have a very profound impact on the protein function.
For many genes, that kind of bears out. As I mentioned, missense variants are a whole other beast where there's a lot of intensive research around that. And then I think the other couple of places where I often see a lot of confusion is around intronic variants. And again, those can be very difficult to interpret because intronic variants are not necessarily in the coding sequence. They're in the intervening introns between those protein codings that are really important in splicing, but are very difficult to kind of interpret. And so in general, intronic variants are less likely to be associated [00:16:00] with disease. But they can be reported out. Intronic variants that are kind of present in the population, we probably have a much lower priority in terms of thinking about which ones are likely to be disease-causing or not.
Dr. Alina Ivaniuk: Okay. With VUS, is it a label that is forever? Are there any ways to bring it to one or another sides of the spectrum, benign or pathogenic?
Dr. Gemma Carvill: Yeah, so, so there absolutely are, and I think over time, many VUS will be and are being reclassified. And that's due to a variety of different factors.
I think from the clinician's perspective, something to think about is asking a genetic testing company to reanalyze the data at specific periods in time. So I would say atne year is probably a little bit too soon, unless you have a really strong suspicion that the VUS that you have in a specific epilepsy gene really correlates very well with the patient [00:17:00] phenotype.
If you get that result and you feel this gene is definitely my, this phenotype is my patient, I'm convinced, then you can sometimes even then go back to the genetic testing company and say, this is a great fit. Would you reconsider, given my clinical expertise and the patient I see in front of me, would you reconsider reclassifying?
You can do that. I think those cases are very few and far between. I think more often the result comes back and you think, oh, this might be a good fit. I mean, I'm not going to completely dismiss it. It does make, it is suspicious. I think in those instances, kind of waiting a year or two and then going back to the genetic testing company and saying, do you have any new information? Can you do a reclassification or a re-analysis of this data? And then sometimes variants will be reclassified one way or the other. So they could become pathogenic or they could become benign. And the way in which variants become benign is that as we sequence more and more individuals in the general population, those variants might pop up.
In [00:18:00] in the general population, especially as we sequence more and more diverse cohorts, we have the ability to identify more and more genetic variants that are specific to specific populations, and I think that that also helps in terms of variant reclassification as well. So yeah, I would say there are certainly ways in which these can be reclassified and going back to the testing company is a good idea.
I think the other resource that is super helpful for questions and researchers alike is a database called ClinVar. ClinVar is a website that is maintained by the NIH and all clinical genetic tests are, most clinical genetic testing results are deposited in ClinVar. And so when you receive a clinical genetic testing result, you can actually go and look in ClinVar and see—has this variant been seen before by another genetic testing company, for instance. And how did they interpret it? Did they interpret it as a benign variant or did they [00:19:00] interpret it as a pathogenic variant? And because there's so much clinical genetic testing happening now, there's thousands to millions of variants being deposited on a very regular basis. And so that helps a lot in terms of reclassification.
So that's something that the clinician on their own can do as well. It's a fairly easy system to navigate. So I think that that is a very valuable resource to use. And then I think the last thing is we've spoken a lot about VUS that are present in known epilepsy genes, but especially individuals who are, for instance, having exome or genome sequencing, we'll often identify a VUS often de novo in a new gene. And those are a different type of beast because the gene might look like a good candidate. It's expressed in the brain. There's not a lot of genetic variation in the general population, but it's just your one patient. And so it's very difficult to call one way or another as to whether that's associated with the phenotype.
And so there is [00:20:00] something called the Matchmaker Exchange, of which Gene Matcher is probably the most well used database, where clinician or a family can go in and enter in a specific gene. There's no PHI, there's no information that's associated with it. And if someone else in the world has identified a genetic variant in that gene, everybody kind of receives an email. And then folks can exchange information. What is the phenotype of your patient? What is the phenotype of my patient? Is it similar presentation? Is it a similar genetic variance? Is it similar inheritance pattern? And then by and large, nowadays, that's how all new gene discoveries are made, is through this kind of matchmaker online data sharing kind of platform.
Dr. Alina Ivaniuk: Whoa. That's a lot of ways actually. And that's, I think, a very valid point, that it's the variant of uncertain significance is uncertain for now, but not forever. And it may change and actually people can make it more to make it happen, [00:21:00] sometimes even proactively with something like Gene Matcher. But what about the cases when, for example, we have several VUS in a single person. How, are there ways to prioritize them or decide which one is probably requiring more attention than the other one?
Dr. Gemma Carvill: Yeah, I think one of the first ways and where we see the biggest class of VUS that probably don't impact the disease phenotypes is really with recessive genes.
So and there are now a number of recessive epilepsy genes. And so as I mentioned, you need both copies to carry a pathogenic variant in order to manifest the disease. Importantly, we all carry pathogenic variants in recessive genes, all of us. And they may be in epilepsy genes, they may be in metabolic genes. They may be in hearing loss genes. And so all of us carry, pathogenic or VUS [00:22:00] variants in recessive genes. And so for me, those are kind of the lowest hanging fruit.
If it's a recessive hit where there's only one hit in a recessive gene, it's present in the population. There's no hits on the other allele, the phenotype isn't a good fit, I think you can definitely deprioritize and put further down. I think thinking about things like the clinical correlation, again, I think is the biggest factor that clinicians have in their back pocket and can leverage their expertise to prioritize variants. Looking at the literature, does this look like my patient.
Another good resource is something called Gene Reviews. Gene Reviews is a very well curated, very easily digestible resource. Again, it's hosted within the NIH system. You can go to Gene Reviews, you can put in the gene of interest, and there's a very succinct summary of the clinical features that are associated with that. There's also, further down, resources like the types of genetic [00:23:00] variants, links to the family foundations, inheritance patterns, so it's a very valuable resource. That's a very quick check to see: Does this look like the patient in front of me?
That of course, all comes with a big asterisk, in that the clinical presentation that we see has a huge ascertainment bias, right? Because a variant is more likely to be classified as pathogenic if an individual presents with a set of clinical features that have been described before. And so I think kind of bordering into the research realm, we're learning that the phenotypic spectrum for many epilepsy genes is a lot broader. And so I think that will also evolve over time.
But kind of right now, I think those are the best tools that clinicians can have in their toolbox to help them sift through what can be very many VUS.
Dr. Alina Ivaniuk: Dr. Carvill, we talked about so many points as of now, right? If you could distill the message down to clinicians to help them understand how to approach a VUS overall, what it is about, and what can be done to sort of bring it to the [00:24:00] surface or bury it somewhere, could you summarize it for us?
Dr. Gemma Carvill: So I think receiving a VUS and especially when you receive multiple VUS, it can be very daunting.
I think the major things to keep in mind are, is there a good clinical correlation? Does the VUS fit with my patient's phenotype? What is the known inheritance pattern of this particular variance and does it fit? What is being reported out? And I think those are the main two points to keep in mind when assessing variants of uncertain significance.
And as I mentioned, I think the one-hit recessive variants are the ones that you can really kind of put to the side when you're evaluating VUS.
And I think the other key thing to take away is use the resources. I'm sure we can share the resources at the end of this podcast. I'm happy to share those resources of good places to go for help as well.
Dr. Alina Ivaniuk: That sounds awesome. Dr. Carvill. I was thinking about some places and providers who [00:25:00] may not have that much support? Yeah, probably not in all the countries, we have genetic counselors, let's say. There are places where only certain types of genetic testing are available in high income countries. Even there are places where genetic services are just not available.
Do you think there are any ways to make either genetic testing more accessible, but how could we better equip clinicians to interpret and act on genetic variants appropriately if they do not have access to the genetic services at their place.
Dr. Gemma Carvill: So yeah, so I think education is key.
And I think kind of linking the resources that are widely available. So I think that's the beauty of the internet, is that it's accessible for most, not all, but most places.
And so I think sharing resources that exist otherwise. So I've mentioned ClinVar, for instance. I've mentioned Gene Matcher. And ILAE has a [00:26:00] wonderful genetic literacy series as well. And I think that that's a great free resource to kind of understand what does genetics mean in current epilepsy care, kind of across the world. I think there are now even things like workshops and kind of how-tos, tutorials that are available that are widely accessible, that I think can help kind of spread the word about how to interpret variants of uncertain, uncertain significance. And kind of the role, even further out, taking away from VUS, the role of genetic testing broadly in epilepsy care.
I think in many inaccessible regions, so I, for instance, work a lot with South Africa, where genetic testing is almost impossible to get as well. And so I think there, it's a combination of one, education, and secondly, partnership across the globe. Partnering with high income countries, for instance, to establish genetic training programs. So that's something that we've done now for many years in South Africa is starting to train clinicians, trying to train pediatric neurologists, [00:27:00] for instance, and how to recognize an individual who might have a genetic epilepsy and identify those individuals that would most benefit from a genetic test.
Because I think especially in resource constrained areas, it's really identifying those individuals where having a genetic result would matter and actually change clinical care that I think we can have the most impact as well.
Dr. Alina Ivaniuk: Dr. Carvill, that's actually, that's beautiful. And I think that this sharing and interaction with resource limited setting providers, that's something that could be really helpful and could change lives of many, many patients.
We know that you have a vast, vast experience in collaboration from many perspectives. Can you share a bit more details or more insights into what these collaborations led into? Maybe there were some notable examples of how data sharing collaboration could change clinical interpretation or somehow help clinicians change their judgment about genetic [00:28:00] data.
Dr. Gemma Carvill: Yeah. So yeah, I think that's the fun thing about working in the epilepsies is that, and especially in the genetic epilepsies, is that folks are very collaborative. And so I think that's been one of the most exciting kind of parts of my academic career so far, is to see how the field's evolved and how collaborative efforts can really change the care for individuals with genetic epilepsies.
And so I think I kind of mentioned the South Africa project. That started probably 10 years ago now, and where we tried to start getting genetic testing in Africa. I think one of the major things that we've learned, and I kind of hinted at this, is identifying those individuals where there's the highest clinical need.
And I think even doing small things like piloting 200 patients, for instance, with DEEs and seeing what are the phenotypes that increase diagnostic yield. I think that those kinds of studies, there's a really big place for them. And it also allows local hospitals to advocate for genetic testing and the power of genetic testing, not only to [00:29:00] help patients, but also impact the healthcare systems around them.
Because as we know, individuals with epilepsy, especially the DEEs, are really frequent flyers at in hospitals and hospital admissions. And so I think that that's a great example of how coupling kind of low to middle income countries and higher income countries together to work collaboratively towards increasing awareness of the power of genetics.
So I think that that's one nice example. I think some other examples of kind of resolving VUS through large data sharing projects and also large, large-ish collaborative efforts is, I'm a part of Epi MVP, which is the epilepsy multiplatform variant prediction. Lots and lots of words that basically means that there are several researchers. So there's us here at Northwestern. Laurie Isom and Jack Parent at the University of Michigan actually lead this project. We work with Heather Mefford at St. Jude, as well as Margaret Ross at Weill Cornell. [00:30:00] And the goal here is really to, our goal was to develop new tools for interpreting variants of uncertain significance in epilepsy related genes.
We chose to focus on the non ion channel genes. For a long time, epilepsy was, and still is, called a channelopathy. And I think that is absolutely true. A large subset of the rare epilepsies are channelopathies, but then more genes that are not channels are implicated in epilepsy. And those kind of been ignored for a long time. We don't have a good understanding of how, when you have a genetic mutation in this gene that functions at the synapse, how does that cause epilepsy? And so because we don't have a good understanding of how loss of function in these genes causes epilepsy, we have even less idea of how to interpret variants of uncertain significance.
And so we've developed both stem cell models as well as animal models to determine how these variants impact protein [00:31:00] function. That's kind of at the cellular, kind of molecular level. But the beauty of kind of our broad approach is that our role here at Northwestern is then to integrate all of this functional data with computational data. We use both aspects. So genetic data machine learning, the functional data to develop new models to interpret variance of uncertain significance. So the idea is while most kind of computational predictors look across all of the genes in the genome, and they are very powerful in terms of determining which variants might impact protein function or not, they're not very specific, so they work well in general for all genes, but they're not super specific.
We try to do something different, where our case example is STXBP1. And we built a machine learning model specific for that gene. And so that machine learning or AI model will generalize very badly. So that means if you take our [00:32:00] model and try and apply it to another epilepsy gene, it won't work at all. It'll work terribly, but it performs really, really well for STXBP1. And so we've done a lot of work over the last couple of years to kind of perfect that model. And now what we have, and what will be released in the next couple of months, is now we have a website.
So a clinician, a family researchers can go to this website, enter in the missing variant that you're interested in, that you receive from a clinical genetic test. And what will return is our prediction as to whether that variant will be pathogenic or not.
Importantly, this is obviously a prediction, but it's based on several different avenues of evidence. And then together with a genetic counselor, with your clinical care provider, you can make a call about whether you think that this is more likely to be pathogenic or not.
And so we've done this for STXBP1. We're doing it for four more genes, but the goal is ready to build this [00:33:00] project out. To build these epilepsy specific classifiers. And I think this is another example of the power of collaboration and folks working together and different expertise but then also coupling with the, making sure that this information is disseminated to those individuals who will actually use it.
So I think this is a really nice example of that as well.
Dr. Alina Ivaniuk: I do agree. This is a very nice example of that and congratulations on getting the website out soon. We'll be looking forward to that. I think it'll find a great use in the epilepsy community and not only in the epilepsy community. Thank you so much for sharing your practical and personal experience as well.
Dr. Gemma Carvill: Thank you very much for the opportunity. It's been fun chatting to you.
RESOURCES
Standards for interpreting variants (American College of Medical Genetics)
EpiPred website for STXBP1 (developed by EpiMVP project - will be final by end of July)
Think Genetics paper – genetic testing in South Africa project
Link to Sharp Waves episode on genetic testing in LMICs