Epilepsy Currents - Episode 9 - "Genetic Testing in Epilepsy: Improving Outcomes and Informing Gaps in Research"
Join Dr. Bermeo in a conversation with Dr. Elizabeth Gerard, and Dr. Christa Habela, as they discuss the article, " Genetic Testing in Epilepsy: Improving Outcomes and Informing Gaps in Research ". Click here to read the article. This podcast was sponsored by Marinus Pharmaceuticals. We’d like to acknowledge Epilepsy Currents podcast editor Dr. Adriana Bermeo-Ovalle, contributing editor Dr. Rohit Marawar, and the team at Sage. In episode nine of the Epilepsy Currents podcast, Dr. Adriana Bermeo discusses the evolving role of genetic testing in epilepsy with Dr. Krista Habela and Dr. Elizabeth Gerard. They explore how genetic insights are enhancing diagnosis and treatment, highlighting the rapid advancements and future potential of this field. Key Takeaways Technological Advances: Since the first epilepsy gene discovery in 1997, technological advancements such as next-generation sequencing have dramatically accelerated gene identification, enhancing genetic testing's accessibility and effectiveness. Basic Genetic Concepts Clarified: Dr. Gerard explains critical genetic components—genes, chromosomes, and exomes—and their relationship to different genetic tests, providing a foundational understanding crucial for grasping how genetic variations impact epilepsy. Diagnostic Yield and Personalized Treatment: Genetic testing varies in diagnostic yield based on patient-specific factors like age of onset and associated conditions. Higher yields in targeted groups underscore its role in developing precise, personalized treatment plans. Impact on Patient Understanding and Future Testing: Genetic testing not only aids in diagnosis but also provides patients and caregivers with valuable explanations for the conditions, reducing uncertainty and informing better treatment choices. The future of genetic testing in epilepsy includes potential advancements in gene therapy and precision medicine, aiming to develop targeted treatments based on specific genetic profiles. Overcoming Barriers to Integration: Challenges like insurance coverage, the availability of genetic counseling, and the need for provider education must be overcome as genetic testing becomes integral to standard epilepsy care. This integration promises to streamline diagnostics and potentially reduce the need for other invasive tests. Adrianna Bermeo-Ovalle, MD (Host): Why do I have epilepsy? What causes epilepsy? Are my children or other family members at increased risk of developing epilepsy as well? These are some of the most frequent questions I hear in the clinic these days. In a healthcare environment which turns more and more towards personalized medicine, genetics presents a unique opportunity to answer some of our patients most pressing questions. Today, we will explore the current indications and use of genetic testing in epilepsy and we'll take a peek into the future of epilepsy diagnosis and care. Marinus Pharmaceuticals is the proud sponsor of episode number nine of Epilepsy Currents podcast. I am your host, Adriana Bermejo. I am the senior podcast editor for Epilepsy Currents, the official journal of the American Epilepsy Society. Let me first welcome Dr. Christa Habela. Dr. Habela is a Child Neurologist, Epileptologist, and the Director of the Long Term EEG Monitoring Program and the Epilepsy Genetics Clinic at the John Hopkins Hospital in Baltimore, Maryland. Dr. Habela is the author of the review, Genetic Testing in Epilepsy, Improving Outcomes and Informing Gaps in Research. This article was published online first on March of 2024 in Epilepsy Currents. Dr. Habela, thank you for joining us today. Christa Whelan Habela, MD, PhD: Thank you so much for having me. Host: It is also my pleasure to welcome Dr. Elizabeth Zoe Gerard. Dr. Gerard is an Associate Professor of Neurology at the Northwestern Feinberg School of Medicine and the Founding Director of the Women in Epilepsy Program, as well as the Adult Epilepsy Genetics Clinic at Northwestern. Dr. Gerard, thank you for being with us. Elizabeth E. Gerard, MD: Thank you so much for having me. It's my pleasure to be here. Host: Dr. Habela, your review starts with a very nice historical perspective, a historical overview of the development of genetic testing in epilepsy. Can you please help us understand how did we get where we are today? Christa Whelan Habela, MD, PhD: It has always been generally thought that epilepsy was a genetic disorder, even prior to any discovery of epilepsy genes. And the first gene associated with epilepsy was only discovered in 1997, and this was for the nicotinic acetylcholine receptor, and then from 1997 to 2007, only 10 more genes were discovered, and this was because we were using, very robust, but very slow and expensive Sanger Sequencing. Early in the 2000s, the first untargeted genomic testing, came into clinical use, and this was the chromosomal microarray. This can be thought of as a very high resolution karyotype, and allowed us to look for deletions and duplications. But it really wasn't until the development of next generation sequencing which is a much faster and a much cheaper way of sequencing our DNA; that we really began to have an explosion in gene discovery. And so, beginning with next generation sequencing, this allowed us to develop whole exome sequencing, sequencing the exomes of our genes, as well as whole genome sequencing. And these two studies allowed us to identify hundreds of genes, up to a thousand genes from the years 2007 to present day. Host: Wow. So it looks like our baby steps took a long time, but we are going on leaps and bounds these days. And I imagine that we will be advancing much faster, now and into the future. Dr. Gerard, let's start with the basics to orient our audience. Could you please explain the difference between a gene, a chromosome, an exome in a way that helps our listeners follow the conversation on genetics? And if you could please link that to which tests correspond to which concept? Elizabeth E. Gerard, MD: So a gene can be thought of as a recipe for making a specific protein that's important to our body. And human genetic code contains about 20,000 recipes or 20,000 genes that make proteins. And so, as Dr. Habela was explaining, we had much faster understanding and ability to give back feedback on misspellings or typos in genes as we develop next generation sequencing. The Sanger sequencing she referred to, could really process one gene at a time. But now with next generation sequencing, we can process and understand the genetic code of multiple genes at a time. So while single gene testing is still rarely used for very specific phenotypes, like tuberous sclerosis or neurofibromatosis, more often, patients with epilepsy, with or without neurodevelopmental disorders may need a bunch of genes sequenced at the same time to increase the diagnostic yield. And one of the ways to do that are epilepsy gene panels or neurodevelopmental gene panels, which use next generation sequencing to look at usually on the order between 200 and 500 genes all at the same time and look for errors in the genetic code that may affect how that recipe works or how it may affect how you make proteins. So that's one commonly done tests now which are gene panels. The genes or the recipes we have are organized into chromosomes. So humans have 23 pairs of chromosomes, and you can think about these as like sort of cookbooks, that contain the recipes. So another genetic variation that can happen that can contribute to disease and contribute to epilepsy, are sort of rearrangements within that chromosome book. So you can think about this as a missing page or half of a page missing. These are really deletions or duplications at the chromosomal level known as copy number variations. And these can include several genes or it can include just as small as part of one gene. And this stuff can be sometimes missed by gene panels or some next generation sequencing that's only focusing on certain parts of gene known as the exome, which we'll get to in a second. So the chromosomal microarray was one of the early tests used to make diagnosis in epilepsy and neurodevelopmental disorders. I think Dr. Habela will talk about the yield of this test, but this looks specifically for deletions or duplications at the chromosomal level. As I mentioned, there are 20,000 genes or recipes in our genetic code. And so we are moving very quickly away from these first two tests I mentioned to exomes. So whole exome sequencing, really sequences all those recipes, all the exonic parts of our recipes. We'll talk about the genetic code in our recipes, and can look at many, many, many genes at once. Even though they're looking at all of those genes in our genetic code; most exome analysis focuses on specific genes relevant to the patient's phenotype or the patient's symptoms. So this is really becoming one of the first tests that we're using in genetic testing for epilepsy and is thought by many to be one of the first two tests of choice. But there are still some things that exomes can miss. So they can miss those copy number variants in some cases if those are not at the levels that affect whole genes. Okay, they can also miss particular disorders like expansion repeat disorders, such as seen in CSTB related progressive myoclonic epilepsy. And then the other thing that's really important to recognize is that our exome with all those 20,000 genes, is really only 1 percent of all of our genetic code. So if you think about that recipe being made up of key components, like the ingredients that you need, that's really the exome. That set of instructions and those key factors that you need to make something or to make a recipe. But there's a lot of information on our genetic code in between the recipes or the small words within the recipe that actually tells us how to use it and how to make what we need to make. And that's the rest o
