Panels & Exomes: Diagnostic Yield & Detection of Childhood Epilepsy

Thursday, November 16, 2017
7:30 pm - 10:00 pm CDT


Plus, discover the latest in genetic testing advances in this episode of our Seizing Life podcast.

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Audience Q&A with Dr. Swaroop and Dr. Sullivan 

Would you wait until the patient has had at least two seizures before considering genetic testing? Or would you consider genetic testing after a single seizure?

I think you really do need to wait for that second seizure, specifically in Dravet syndrome, we’re really trying to arrive at a very early diagnosis and we’ve actually looked to see if genetic testing should be sent after a young child under the age of one has had their first episode of prolonged convulsive status. That may be an isolated situation where I think a single seizure could be argued, but other than that, I think you really need to wait for that second seizure.

The table showed a relatively high yield of TPP1, can you speak to this?

Yeah, absolutely. And this was surprising to us as well and a couple of them were actually… It turned out a couple of them were actually because of signatures that are associated with TPP1 related Neuronal Ceroid Lipofuscinosis. So there was a prior probability that we would discover it. But in several of those other ones, we actually didn’t expect those. And so it may be that as rare as this disorder is, and perhaps it is under diagnosed. And some of you may know that there’s a program that BioMarin has that is looking at these individuals with mutations in TPP1 and seeing who may be eligible for a drug therapy. And I think it appears that this disorder may not be as rare as we’ve thought before. But really, I mean, even in the quarter of 2000 children we’re seeing a number but I would really be interested in seeing a much larger cohort and seeing if this number really holds true.

How difficult has it been for you to get genetic testing approved for your patients with epilepsy?

It really does depend on the type of insurance coverage. But it also depends on the attitude of the person on the other end of the line when you’re calling in to get the prior authorization. I would say that in my practice, because we still serve about 50% of our patient population is state-insured or under-insured, Medicaid Medical, that it is still very challenging, but I know that there are a lot of companies that are working with us to try and come up with an arrangement so that those patients who could benefit the most can get testing but that’s a process in evolution right now.

Is it best to order a panel that includes deletion duplication studies performed simultaneously with the sequencing? Or does it make more sense to see what the findings of the sequencing are and then only order deletion duplication for the genes indicated based on the sequencing results?

Yeah. I think that’s a good question for a couple of reasons. One, I think it’s fair to say that we really didn’t appreciate how prevalent these exonic copy number variants are in disease genes, aside from maybe a handful like Duchenne muscular dystrophy, or some of the other ones. But where we’re really seeing this evolve to is being able to detect a much broader spectrum of variants, including single nucleotide variants, indels, exonic, copy number variants, etc, all within a single test.

And so it should be, we should all be moving towards being able to get all those pieces of information together from a single test. And we’re finding through internal analysis of our data, that the prevalence and frequency of these exonic copy number variants is actually pretty high that it accounts for almost 10% of all the pathogenic variants that we’ve ever reported from Invitae. So it’s clearly a high proportion of clinically important findings. So my opinion, is that these tests should be looking at exonic copy number variants at the same time as sequence variants so we have the most optimal clinical sensitivity of testing.

When would you recommend testing an adult patient and is that something that you need to consider with a higher concern if they have relapsed? And what would your recommendations be for them?

I’m glad that this is being asked. I think that because I commented that a lot of the early onset epilepsies have a very high diagnostic yield, if an adult being seen in an adult epilepsy practice, had an infantile onset epilepsy, and there still is not a known cause, I would say that those group of patients actually represent a very rich group where the yield could be exceedingly high. Especially if the clinician has the time to go back and take that early childhood history, I’m convinced that there are hundreds of patients sitting in an adult epilepsy clinic with SCN1A mutations that had Dravet syndrome but then when they turned into adults they have a little bit more of a nondescript phenotype and our adult epilepsy colleagues may not have that index of suspicion. But I still think that those group of patients just to summarize, are those with infantile or childhood onset who continue to have seizures and have no known cause.