The Expanding Role of Genetic Testing in Epilepsy

Body text: Genetic testing is rapidly changing the evaluation of epilepsy, with some of its greatest diagnostic yield seen among children with seizures and developmental delay. As hundreds of genes have become associated with epilepsy, genetic findings are giving clinicians and families new ways to understand disease etiology, anticipate its course, and identify additional clinical features that may require attention.

In this NeurologyLive® Insights series, Jacqueline French, MD, professor of neurology at NYU Grossman School of Medicine, co-director of epilepsy research and epilepsy clinical trials at NYU Langone Health, and chief medical and innovation officer of the Epilepsy Foundation, provides a clinician-focused look at epilepsy across the continuum of care. Throughout the series, French addresses disease burden, classification and diagnosis, comorbidity management, transitions of care, and the changing role of genetics in understanding the disease.

In this concluding episode, French discusses where genetic testing has the greatest utility today and why its value can extend well beyond identifying a targeted therapy. She examines how a genetic diagnosis can provide prognostic information, guide screening for associated comorbidities, and connect families with disease-specific communities, while also addressing genetic testing in adults and the challenges of interpreting variants of uncertain significance.

Genetic testing is skyrocketing, and right now a lot of the focus is on children with seizures, particularly children with developmental delay and seizures, or what we call developmental and epileptic encephalopathy, because in that population there is a very high yield from genetic testing.

There are, I think, 600 genes now that are associated with epilepsy to one degree or another. There are many important things that families derive from genetic testing, and they may not be exactly what people are thinking of. People may think that if they get a genetic test and get the answer that the epilepsy is associated with a single gene, for example, that will lead to a new treatment or a cure. In many cases, that is not correct.

There are very few monogenic epilepsies, usually the largest of the monogenic epilepsies, such as Dravet syndrome and CDKL5 deficiency disorder, among others, that either have specific antiseizure medicines that have been tested for them or are starting to have gene therapies or gene-related therapies that can be applied. So, that will be for the minority. Of course, that's going up over time, but it's still a small minority.

Nonetheless, having a genetic diagnosis can do an enormous amount for a family. The first is that it can provide prognostic information in some cases about what is going to happen to that child as they develop and grow. Is there going to be an improvement, which happens in some cases? Is there going to be a deterioration?

The second thing you'll learn is whether there are comorbidities that are specifically associated with that particular genetic mutation. Are there sleep disturbances? Are there GI disturbances? Are there skin manifestations? There are many different types of things.

Knowing what to expect in that regard means that you can be proactive. Sometimes you can head things off at the pass, or you can recognize things more quickly when they happen and screen for them. So, that is an extremely important aspect of having a genetic diagnosis.

The third part, which may even be as important as the first two, is that if you know your child has a specific genetic diagnosis, you can start searching for others with that diagnosis. In almost all cases, as soon as a monogenic epilepsy is discovered, the parents of children with that monogenic epilepsy start to band together. They usually create a nonprofit, and that nonprofit allows parents to talk to each other.

The information, support, and strength they can get from communicating with a community that is going through exactly the same thing they're going through is a treasure beyond measure. So, that is also a very important part of getting a genetic diagnosis.

In adults, it's a little more complicated because there aren't that many positive genetic diagnoses in adults. There are certain syndromes in adults where there are telltale signs that, when a clinician sees them, might prompt genetic testing. Obviously, if there's a family history, that would increase the likelihood, and genetic testing may be more in the cards.

Things like auditory features prior to a seizure can be associated with autosomal dominant auditory epilepsy. People with very prolonged tonic-clonic seizures and generalized spike-and-wave could have one of the monogenic epilepsies, such as GEFS+. They could have an SCN1A or an SCN1B mutation. Those are some examples, but not all of the examples.

Of course, everybody can have genetic testing. One has to be very careful that if genetic testing is performed, there is the opportunity to consult with a genetic counselor. A lot of times, what will happen is that the individual will get a variant of uncertain significance, a VUS, and there may be a statement saying that this VUS has a reasonable likelihood of being pathogenic or not being pathogenic.

Families will interpret that as they will, and sometimes that can actually do more harm than good when they believe that this variant, which really hasn't been proven to be associated with epilepsy, is now the cause of their epilepsy.

The last thing I'm going to say is that a lot of the monogenic epilepsies in childhood are what we call de novo, which means that the parents don't have it, and the children are unlikely to reproduce.