Signal. I admit that the title of this blog post is somewhat misleading, but please bear with me. Yes, GLP-1 receptor agonists have very little to do with epilepsy, but there is a larger story behind this. In a recent study, nearly 28,000 people taking GLP-1 receptor agonists answered a seemingly simple question: how much weight did you lose, and how bad were the side effects? This simple survey, coupled with genetic data, produced one of the cleanest pharmacogenomic signals seen in recent years. But it also emphasized that the genetics of treatment are often not the genetics of disease, and that matters far beyond obesity and weight loss. Here is why this should make us rethink pharmacogenomics in epilepsy.
Category Archives: SCN8A
STRIPE – When RNA Speaks Louder Than DNA
RNA. More than a decade ago, I remember reading an article arguing that we actually live in an RNA world. At the time, this felt a bit academic and not really relevant. Genetics was about sequencing and interpreting DNA. However, over the last few years, our ability to think in terms of RNA transcripts rather than DNA sequence has become increasingly relevant. When I teach trainees, I sometimes tell them: we do not care about genes. And then I pause, usually long enough to make people uncomfortable. Then I correct myself: we care about transcripts. In a recent publication, we assessed how a novel targeted long-read RNA sequencing approach can help with rare disease diagnosis. Here is what we found.
Signals in the noise – qEEG patterns in genetic epilepsies
qEEG. The electroencephalogram is one of the oldest tools in neurology. We use it every day to diagnose and monitor brain function, yet, even in the era of genomic medicine, most of our EEG interpretation still relies on visual inspection, a human reading of squiggled traces. In a recent publication in Neurology, we asked whether the information embedded in these signals could be measured more objectively in children with STXBP1, SCN1A, and SYNGAP1-related disorders. Here is the story on how we identified hidden signals in the EEG tracings of individuals with genetic epilepsies.
The quiet revolution – revising ACMG criteria for epilepsy genes
VUS. The story begins with a patient in clinic. A young child with severe epilepsy, carrying a variant in SCN1A, the classic gene for Dravet Syndrome. But the variant is labeled a variant of uncertain significance (VUS). Dravet Syndrome is a clinical diagnosis, and the treatments we have today do not hinge on whether the variant is clearly pathogenic or not. But then we wonder whether a novel precision therapy could be an option, and we look up inclusion criteria and hesitate. Trial frameworks often require a variant to be pathogenic or likely pathogenic, and future precision medicine approaches in routine clinical care may require the same. For this patient, a VUS is a door that does not open. Here lies the quiet revolution in epilepsy genetics that is unfolding in the background: the refinement of variant interpretation itself.
The power of paralogs in epilepsy genetics
Paralogs. Every week in our variant review meetings, we encounter a familiar issue: understanding a missense variant of uncertain significance. Unless it matches a known disease-associated variant or is found to be de novo, our confidence often stalls. But what happens if we stopped looking at genes in isolation? In a recent publication, we had the opportunity to explore this idea by looking at paralogs and variants at identical sites across gene families, and we found evidence that was strong enough to be included in the official ACMG/AMP variant curation criteria. Continue reading
This was epilepsy genetics in 2021 – five things to remember
Looking back. Admittedly, I have not written an end-of-the-year review for a quite some time. However, there were a few notable moments in epilepsy genetics in 2021 that I think were worth remembering. The second year of the COVID-19 pandemic started out as a year of recovery and readjustment, only to run into unanticipated supply chain issues and novel COVID variants hanging over our transition into 2022. The scientific community was affected by these developments in different ways that made progress of science somewhat unpredictable and uneven. 2021 was the year when the phrase “unprecedented times” became stale and overused. Here are five things to remember from 2021, which will be remembered as part of a transitional phase in epilepsy genetics. Continue reading
The Epilepsy Genetics Initiative – novel diagnoses through exome re-analysis
The negative exome. Despite writing a lot about the power of next generation sequencing technologies to provide a genetic diagnosis in individuals with severe epilepsies, it is important to remember that most exome tests performed in a diagnostic setting are negative. Even the most optimistic studies do not find a diagnostic yield that exceeds 40%. However, what can be done about the 60-70% of patients who had undergone exome sequencing, the current gold-standard diagnostic testing, but have received a negative test result? A systematic re-analysis after 12-24 months is currently considered one possibility to make sense of existing exome data. In a current publication, the Epilepsy Genetics Initiative (EGI) reports their results of a systematic research-based re-analysis in 166 individuals with epilepsy. In eight individuals, a novel diagnosis could be achieved, including novel genes not known at the time of the initial report and novel mechanisms such as alternative exons. With a diagnostic rate of 6%, this study provides a unique benchmark of what can be expected when exomes initially come back as negative. Continue reading
What’s new with SCN8A – a 2016 update
An unexpected twist in the SCN8A story. SCN8A mutations were first implicated in epilepsy in 2012, when a de novo missense variant was identified in a patient with early infantile epileptic encephalopathy (EIEE) via genome sequencing. Since then, a number of patients with de novo heterozygous SCN8A variants and epilepsy have been reported, firmly establishing the role of SCN8A in EIEE, and we have learned a lot about the associated phenotype, mutation spectrum and disease mechanism within the last four years. Recently, a heterozygous familial SCN8A missense variant was identified in several families with a significantly milder epilepsy phenotype than reported in previous patients. Read further to learn more about the expanded SCN8A-associated epilepsy phenotype. Continue reading
SCN8A – this is what you need to know in 2015
SCN8A. In 2015, SCN8A has emerged as an important gene in epileptic encephalopathy. SCN8A encodes the voltage-gated sodium channel alpha subunit Nav1.6, and was first implicated in epileptic encephalopathy in 2012. Since then, approximately 100 cases of early-infantile epileptic encephalopathy caused by mutations of SCN8A have been identified, and the disorder has been designated EIEE13. Here is what you need to know about SCN8A in 2015.
Publications of the week: GRIN2A, SCN8A, and DEPDC5
Issue 10/2015. This week’s publications of the week are about known epilepsy genes that have been around for a while. There are, however, some interesting updates about these genes that are worthwhile discussing. Follow me on a discussion about recent studies on GRIN2A, SCN8A, and DEPDC5. Continue reading