Research & InnovationGenetics & Precision MedicineDiagnosis, Treatments, Preventions
Written By Torie Robinson

Genetic Testing in Epilepsy: What Results Really Mean - Dr. Christian Bosselmann, University Hospital Tübingen, Germany

Who should receive genetic testing in epilepsy, and how should results really be interpreted? Epileptologist and scientist Dr. Christian Bosselmann explores genome sequencing, diagnostic yield, variants of uncertain significance, and why results are rarely black and white. The discussion highlights how quickly things are changing in epilepsy genetics and how re-analysis and improved interpretation can meaningfully influence clinical decision-making.

 

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This episode is sponsored by EASEE® by Precisis who’s had no influence over the editorial content or discussion. Learn more about EASEE® here.

 

Episode Highlights

  • Who genuinely benefits from genetic testing in epilepsy

  • Why variants of uncertain significance are often misinterpreted

  • How re-analysis can change diagnoses and treatment decisions

  • Why genetic results are rarely definitive


About Dr. Christian Bosselmann

Christian is an Epileptologist-Scientist in the Department of Neurology and Epileptology at the University Hospital Tübingen and previously trained at the Cleveland Clinic, Cleveland. His interest lies in the medical and surgical treatment of the epilepsies and he has published widely on rare genetic epilepsies.

Full profile: christian-bosselmann

Topics mentioned

  • genome sequencing

  • diagnostic yield

  • variant interpretation

  • variants of uncertain significance

  • re-analysis

  • pathogenic vs benign variants

  • pharmacogenomics

  • clinical decision-making

  • quality of life

Related papers

Useful link

Lal Research Group

  • Trailer & intro

    00:00 Christian Bosselmann

    “An inconclusive or negative genetic testing result doesn't have to be the end of the journey. There are a few questions that come naturally, first is: have you tested to the standard of what's available?”

    00:11 Torie Robinson

    Welcome to Epilepsy Sparks Insights! I’m your host, Torie Robinson, and here we talk with specialist clinicians and researchers to spark improved understandings of the epilepsies worldwide. Today I’m joined by Dr. Christian Bosselmann, who is going to be sharing with us how epilepsy genetic testing results should really be interpreted, why uncertainty is common, and how genome sequencing can totally change clinical decisions!

    This episode is presented in partnership with EASEE®, by Precisis GmbH.

    Who are the epilepsy patients who benefit from genetic testing?

    00:38 Torie Robinson

    Who genuinely benefits from genetic testing today, and where do we still get testing decisions wrong?

    00:45 Christian Bosselmann

    So that the primary misconception, I believe, is that everyone who has a genetic diagnosis has to have a family history. The number of people who could stand to benefit from genetic testing has widened considerably. Any syndromic diagnosis, so epileptic encephalopathies, any familial focal epilepsies, perhaps even any drug-resistant epilepsies during presurgical evaluation. And we've done quite a bit of work on that. So, in short, most people with epilepsy.

    What type of genetic testing?

    01:20 Torie Robinson

    Most people with epilepsy would benefit from having whole exome sequencing?

    01:24 Christian Bosselmann

    So that's the second major question and that's what we still get wrong quite a bit, which is that we are now at a period in time where we really want to do first-line genome sequencing. I understand that there are some practical hurdles and challenges in implementing that, but the UK and Germany, and many centres in the US have been very good about implementing genome sequencing and really gives us a nice and full picture, especially including non-coding variation like the recently described ReNU syndrome, complex and structure variants. So, the yield there is really quite a bit higher.

    02:03 Torie Robinson

    What is “yield”? For people who aren't familiar, what does that mean?

    02:07 Christian Bosselmann

    When we talk about yield, that's the expected percentage of people who get a positive genetic finding after testing.

    Does genetic testing provide answers?

    02:06 Torie Robinson

    So whether we have answers to give to people. So why is a genetic test so often mistaken for a definitive answer? Why are things not black and white?

    02:27 Christian Bosselmann

    So that really depends on what you consider an answer to be. A positive genetic finding can end a diagnostic odyssey. It can end a lot of uncertainty and guilt. It can prevent potentially harmful further investigations. So that's already a big part of an answer. At the same time, I believe the question is changing. We are becoming increasingly aware that a single genetic variant may not always be the only or even the primary explanation for a child or an adults' well-being. So, the genetic background, common variants that we also have, or dual aetiologies where we have not only a genetic variant but also another genetic variant, or a structural change; both of which can explain the epilepsy. And lastly - and this is more of policy issue - external factors. So, the socioeconomic circumstances we grew up in, some healthcare disparities and inequalities, and the treatment-related factors; what is the consequence of what we're doing with individuals with epilepsy.

    03:39 Torie Robinson

    Those are factors are not enough taken into consideration in general. People look at the results of a genetic testing, thinking “Okay, that, that, that…”, and it's black and white, but there are actually so many other things which impact the treatment and the quality of life of the people affected.

    03:55 Christian Bosselmann

    Absolutely, yeah.

    Variants of Uncertain Significance

    03:56 Torie Robinson

    When people will get a genetic test done, and, well, actually it's often the family that is (fingers crossed) part of this, it's not just the individual? What happens when the results are uncertain or contain a variant of uncertain significance or VUS? What does that mean for decisions?

    04:15 Christian Bosselmann

    Both the affected individuals, and their families, and we as physicians, are always looking for answers. And if there's a genetic test result that says there's a variant of uncertain significance, the most common error is to assume that this should be used to guide clinical management. It is just that there is a certain level of uncertainty that means that we shouldn't consider to be directly disease-related. And that's a pitfall that we can really fall in quite a bit. There are certain bands of uncertain significance that we call “hot” VUS (in genetic speak!) that are probably worth following up on with functional testing, computational modelling, with segregation analysis or family testing. But in lot of cases, it's just a matter of waiting to see what additional evidence comes up over the next few years.

    05:13 Torie Robinson

    So a person whose test today doesn't show any clear abnormalities or mutations, that doesn't mean everything's over. Because in the future we might find out more.

    05:24 Christian Bosselmann

    Absolutely, and I think that's really the good news. An inconclusive or negative genetic testing result doesn't have to be the end of the journey. There are a few questions that come naturally; first is: have you tested to the standard of what's available? And that brings us back to genome sequencing and currently, for example, trio (so both parents and the individual), short-read genome sequencing. Then, if even that doesn't show up anything, it's re-analysis. So that's what I mentioned about waiting a bit. The genetic information and the raw data doesn't change, but our understanding of it does. The research side of things is moving quite rapidly, so we may have additional tools for analysis, better guidelines, and more information about the individual that helps us prioritise variants. And if it truly remains unsolved, if you can't find an answer even though you've been digging for years, that's where a lot of collaborative research is headed. So we have, for example, European consortium like Solve-RD and ERDERA, where people come together to really look at these “hard to crack” cases.

    06:37 Sponsor mention

    Before we move on - with thanks to EASEE®, by Precisis GmbH.

    How interpretation of variants impacts treatment and care

    06:41 Torie Robinson

    From your own clinical experience, what is one finding that changed how you think about genetic testing or the interpretation of the data you collect?

    06:49 Christian Bosselmann

    I think that one thing I really want to get back to is the idea of variant interpretation; of how we start to look at these variants. And just to formalise this a bit; this is the way of how we make sense of genetic data to guide clinical management decision making. The most common question is pathogenicity: does this variant provide an answer? Is it disease related? But it can also guide management, clinical and medical treatment, for example. So that's pharmacogenomics: how is that drug metabolised and what are the likely response rates, and various mechanisms for precision medicine. If you get a test result back that says variant of uncertain significance or likely benign or likely pathogenic, there's already been a substantial effort on behalf of the testing laboratory and the medical geneticists who go through guidelines like the ACMG or the ACGS in the UK and clarify and classify this variant. But the idea is we really want to get disease-specific insight in there. So, one thing that has inspired me in my own clinical and research work has been the idea of making it about epilepsy. So, finding a way that we can find new methods or repurpose existing methods to respect the genetic architecture of epilepsy and the needs of the affected individuals.

    Addressing all symptoms of genetic variants 

    08:23 Torie Robinson

    And by “needs”, what could that be? Because it's not just about seizure control, for instance.

    08:29 Christian Bosselmann

    Oh no, it very much isn't. “Needs” in the sense that a lot of the individuals that currently receive genetic testing have particularly severe drug-resistant epilepsy and we want to improve treatment. That doesn't always mean seizure freedom in that case, it also means just better quality of life, better sleep, less stress, better behaviour, just a whole set that defines quality of life. And to do that we need to bridge the gap between the genetic testing report and what to actually do with it in individuals with epilepsy.

    Tailoring interpretation and bridging the translational gap

    09:04 Torie Robinson

    And where are we lacking there?

    09:06 Christian Bosselmann

    So, this is about tailoring the interpretation and bridging this translational gap. Unfortunately, there are things to be done, but epilepsy has a very active and engaged research community where we have tools that have been designed for epilepsy. Initially, like the missence tolerance ratio for regional constraint, very detailed sort of genetic things, but also very tangible visualisations like the 3D structural modelling by Sumaiya Iqba, like the paradox where we try to gather evidence from variants on related genes, which is what Tobias Brünger has done. And this is all presented very nice together on so-called “portals”. So, we have web interfaces designed specifically for neurodevelopmental disorders and epilepsy by Dennis Lal and colleagues, for example, that make this a reality.

    How this work benefits clinicians

    10:09 Torie Robinson

    And doing this work for patients and families, what are the benefits to the careers of the clinicians?

    10:17 Christian Bosselmann

    There are two very different ways that this work is rewarding by impacting lives. And it can go either direction. So, for example, I've recently seen an individual with a variant of uncertain significance in SCN8A (a voltage-gated sodium channel). That was a finding from a very old gene panel 10 years ago. And the clinical characteristics of that individual never really fit our understandings of SCN8A-related disorders. But the previous physicians were still very hesitant to give sodium channel blockers just because she had that label on her doctor's note. And we were able to reclassify that as a likely benign variant, because things change over 10 years; she doesn't have SCN8A-related epilepsy! That came as a bit of a shock initially, because in that case you're taking away an answer, and then they suddenly start introducing uncertainty. At the same time, she'll receive Lamotrigine (a sodium channel blocker), and is doing well. So, it can really go either way.

    Another individual with a variant in another rare gene, which was classified as a VUS for the last three years. And it took 10 minutes to figure out that this is a pathogenic variant. Again, because things have changed over the last three years. And this just goes to show variant interpretation is feasible in the clinic and at the bedside. It's not just an academic curiosity for specialists. You can do it and you should do it! And I really think that we need to get that into epilepsy training better. I mean, it's out there to some degree, but especially in adult epilepsy we have specialisations in imaging, in signal analysis, in surgery. We need more variant scientists as well.

    12:28 Torie Robinson

    I cannot agree more. I work with lots of adults who have an epilepsy and they are refractory, they don't know why nobody proposes “Should we do a genetic test on you?”. It doesn't even go through the heads of the patients or the clinicians. They just don't even think about it. The difference that could make to their lives would be incredible.

    12:45 Christian Bosselmann

    Absolutely, yeah.

    Final thoughts & thanks

    12:47 Torie Robinson

    Thank you very much to Christian for clarifying for us how genetic testing results should be interpreted, why uncertainty is so common, and how genome sequencing and re-analysis can meaningfully change clinical decisions and patient quality of life, and also (!) how more and more is being discovered in genetics - giving realistic hope to those - as of yet - don’t have a diagnosis.

    With thanks again to EASEE®, by Preh-TSEE-Ziss GmbH, for partnering with Epilepsy Sparks.

    If you found our chat today helpful, please give us a like and subscribe to the channel, and hit the bell so that you are notified when new episodes come out (which pretty much every week!). I would personally love to hear your constructive thoughts or experiences in the comments below. Thank you for joining us, and see you next time.

    Note: Some case details were changed to protect data privacy. Written informed consent was obtained from all involved individuals.

Torie Robinson
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