Genetic testing in epilepsy: Who, how, and why? Dr. Ilona Krey

This first episode in a multipart series on genetics in epilepsy covers the basics of genetic testing. Dr. Alina Ivaniuk interviews Dr. Ilona Krey, a physician and researcher at the Institute of Human Genetics at Leipzig University Medical Center.

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Transcript

[00:00:00] Nancy Volkers: Hello listeners, this is the first in a six-episode series on genetic testing and epilepsy. This episode covers the basics of genetic testing and future episodes will dive deeper into other aspects and issues. Make sure to subscribe so you receive the entire series, along with all of our other episodes released this year.

Thanks!

[00:00:25] Dr. Alina Ivaniuk: Today we are diving into a hot and highly demanded topic, clinical genetic testing in epilepsy.

Who should be tested? When is it most appropriate? And why it can be a game changer in patient care. I'm joined today by Dr. Ilona Krey, a medical doctor and researcher at the Institute of Human Genetics at Leipzig University Medical Center. And she's very prominently involved in neurogenetics research with a particular focus on Angelman syndrome and GRIN-related disorders.

Her contributions have been instrumental in understanding genotype phenotype correlations and creating user friendly multilingual platforms. And references to engage both patients and healthcare professionals in genetics research globally. Ilona, welcome to the podcast. We are delighted to have you today.

[00:01:20] Dr. Ilona Krey: Thank you very much. I feel very honored to be here today. 

[00:01:25] Dr. Alina Ivaniuk: Fantastic. Let's dive into this. And let's start with the first and most important question. Yeah, who needs to get genetic testing because in many people's understanding persons with genetic epilepsy or potentially genetic epilepsy who are sick, have multifocal epilepsy, probably very severe developmental disorders.

Can you talk a bit about that? What kinds of epilepsy are more likely to have genetic causes and what kinds of clinical presentations would prompt you to order genetic testing in a person with epilepsy? 

[00:02:01] Dr. Ilona Krey: I assume you mean monogenic. So in this case, it's not limited to a type, but rather to phenotypes. So especially severe epilepsies with early onset, like DEEs (developmental epileptic encephalopathies) or progressive phenotypes. Epilepsy and ID (intellectual disability) or epilepsy and autism and other comorbidities, but also progressive myoclonic epilepsies and non-acquired focal epilepsies in specific family syndromes. 

[00:02:38] Dr. Alina Ivaniuk: Thank you so much for giving this overview of phenotypes that can result indeed, as you mentioned, in monogenic epilepsies.

Yeah, that is epilepsies that are caused only by one-gene disruptions. That's very helpful. Can you talk about available types of genetic testing? What can, what kind of variants they can reveal and which kinds of genetic testing you would employ in which scenario?

[00:03:09] Dr. Ilona Krey: This really depends on the availability where in the world you are And also the costs and the health care system but commonly we recommend exome or genome sequencing as first tier if it's possible. Because with this approach, you can detect SNVs and CNVs, meaning single nucleotide variants and copy number variants. And we see the largest diagnostic yield in this in this approach. 

[00:03:48] Dr. Alina Ivaniuk: Can you explain a bit the difference between exome sequencing and genome sequencing and what is preferable in regular clinical settings? 

[00:03:57] Dr. Ilona Krey: Genome sequencing comprises sequencing of the entire human genome, and this enables the identification of SNV and CNV in the coding regions as well in intronic, intra, and intergenic non-coding regions. Exome sequencing means the sequencing of the entire coding sequence and the surrounding intronic regions, but not the intra and intergenic regions. These are usually not targeted in the exome sequencing, and we see a slightly higher diagnostic yield in genome sequencing. And there's a gain regarding reanalysis in, for example, a newly described locus or gene we want to check in advance, but it's also a high data load that needs to be stored somewhere. So you always have to figure out which is the best approach and which is available in the lab where you do the sequencing. 

[00:05:06] Dr. Alina Ivaniuk: Yeah, absolutely. It does come to the question of availability, right? And probably, exome sequencing is more accessible right now in the world, but nonetheless, more extensive testing has a higher yield.

[00:05:26] Dr. Ilona Krey: Exactly. And if it's only a panel sequencing available, then it's even better to do the panel than doing nothing. So it really depends what is available and what is affordable. 

[00:05:40] Dr. Alina Ivaniuk: Absolutely. Yeah. It's better to do something to help elucidate the diagnosis than do nothing without an access to more extensive testing.

That's for sure. Let's talk a bit about the results that may come back. Yeah, everybody expects answers for, from genetic testing, but sometimes the answers do not come or rather an answer variant of uncertain significance or unclear significance in certain interpretations of that abbreviation comes in.

Can we talk a bit about which kinds of results we can get? What is a benign variant? What is a pathogenic variant? And what is a VUS and how we can use those in practice, in clinical decision making. 

[00:06:23] Dr. Ilona Krey: Yeah, sure. So for this, you need to know that we define or we use these defined criteria called ACMG (American College of Medical Genetics and Genomics) criteria.

There are also ACGS (Association for Clinical Genetic Science) best practice guidelines and ClinGen sequence variant interpretation recommendations that we use to find out what a variant is about, if it's disease causing or not. And therefore we use these criteria. And there are also rising numbers of variant creation expert panels. There are ACMG criteria for a specific gene with more precise criteria only for this gene or a group of genes. So when we use these criteria, we can come to the result that the variant is pathogenic, meaning it's disease causing, or it's benign, meaning it's not associated with the symptoms or disorder.

Or the third scenario is that we get a variant of uncertain significance (VUS) meaning that we, at this point, don't know exactly if it's disease causing or if it's benign. But it’s not that VUS are all the same. So we need to find out. If we are not able because of the criteria to say that the variant is pathogenic, but we think it's causative, this is why we need to really look into the genetic report, why the geneticists think that the variant is meaningful to be written in the report. So usually we only report variants of uncertain significance if we think they could be positive and we need more evidence to find out if it's disease causing or not.

For example, if we only sequence the index patient or the affected patient, we can report this variant and recommend a segregation analysis in the parents to find out if it's a pathogenic or not. So there are these three scenarios. 

[00:08:42] Dr. Alina Ivaniuk: Okay, so right from the get go, if we test the index case and parents, it will more likely yield us more information to make a call if it's benign, pathogenic, or VUS, but it can still come as a VUS, right?

[00:09:00] Dr. Ilona Krey: Right. this is why we usually say VUS is not a good base for decision making, but it really depends what kind of VUS you have and why we classify this variant as a VUS. 

[00:09:16] Dr. Alina Ivaniuk: How frequently do you think the variants of uncertain significance should be reassessed to see if anything has changed and there is new knowledge to make a call if it's benign or pathogenic?

[00:09:31] Dr. Ilona Krey: I would say there's no general recommendation. It really depends in each case, but in general after 18 months to 2 years, and this also applies for an unsolved case. If we can find anything, then we also recommend to reanalyze the case after 18 months to 2 years. And this also depends how old the individual is.

[00:10:04] Dr. Alina Ivaniuk: Okay, that was actually my next question. Yeah, what if we gained nothing from, let's say, exome sequencing? What should we do? So you would suggest that re-analysis, returning to the case in 18 months to 2 years may, could yield something. 

[00:10:26] Dr. Ilona Krey: Yeah, yeah. In this case, it's always good to talk with the clinicians or an interdisciplinary team to assess if there are any additional new upcoming symptoms or other new things. And if a genetic cause is still considered. And if so, you can do the next step, which is like a trial exome or genome sequencing, meaning the affected individual together with the parents, or you recommend re-evaluation after 18 months. And it's also worth thinking about the testing method. Is there a hint for another strategy, for example, repeat expansions or imprinting defect, which are sometimes not seen in the exome. So it is also worth thinking about the other possibilities and other testing strategies. 

[00:11:27] Dr. Alina Ivaniuk: Yeah, that's absolutely valid point as well, right? What if it's a progressive myoclonic epilepsy due to repeat expansion, or could it be Ring 20, which will not be detected probably by endocrine, right? So we would need to refer to other kinds of genetic testing just based on the phenotype. So phenotype comes first.

And then after all of this, how can genetic testing impact the treatment of epilepsy in our patients? Is there any potential hope for people with genetic epilepsies? 

[00:12:03] Dr. Ilona Krey: Yes, I really do think so. And it's in different ways, because for example, a recommendation could be to avoid certain anti-seizure medications or if certain anti-seizure medications work better than others. Or it also could be that there are recommendations for a specific precision medicine approach, which is only for this gene and sometimes only for this variant because we really have to think that writing the genetic report isn't the end of the story. We need to find out what the variant is doing.

So when we write the report, or if you find the variant, we can't see what the variant is doing if this isn't a known variant. So we need to find out what is functionally behind this variant to understand the mechanism and then potentially work against or with this mechanism. 

[00:13:13] Dr. Alina Ivaniuk: So not only the variant, but actual impact on the protein, whether it enhances the function of the protein or damps the function of the protein is important to understand how we could help an individual with this sort of genetic variant and if there are any treatment strategies right now or down the road. That's also interesting. 

[00:13:38] Dr. Ilona Krey: I think it's very important to understand the mechanism to have ideas how to affect the treatment strategies. The whole setting. 

[00:13:48] Dr. Alina Ivaniuk: Okay. And to understand that probably needs research facilities. If you yield a new variant with unknown function, how could the clinician know about the functional consequence of the variant and if there is any resource that could refer to, or it really relates to the availability of research facilities and decide.

[00:14:17] Dr. Ilona Krey: Yeah, and this is sometimes the limited factor because we have not enough resources to look at every mechanism of every variant. 

[00:14:29] Dr. Alina Ivaniuk: Thank you so much for this primer on genetic testing in epilepsy. As closing remarks, do you have anything else to tell our audience, anything that you would like them to remember from this talk specifically, or anything that we have not discussed, but you would like to mention this?

[00:14:45] Dr. Ilona Krey: Only one last thing that I really recommend that we all talk together. If clinicians don't understand the report, just call us. Just ask, “Why are you writing this? I really want to understand it.” So I really recommend that we all talk together to improve our conversations, our discussions, and the care of our patients.

[00:15:11] Dr. Alina Ivaniuk: That's a fantastic closing remark. Yeah, work with a geneticist. We need more interaction and collaboration to facilitate genetics in epilepsy and overall talking to each other helps in many circumstances, especially with genetic testing and genetic test results discussions where some things can be pretty cryptic for clinicians.

If you are in doubt, go to your geneticist and ask. Okay. Well, Ilona, thank you so much. It was a pleasure talking to you today. 

[00:15:45] Dr. Ilona Krey: Thank you very much. It was very nice talking to you.