The landscape of epilepsy genetics in 2023

Clinical neurogenetics. Characterization of the genetic landscape of the epilepsies continues at a rapid pace, and the effects of this vast gain of knowledge are beginning to show within routine clinical care of people with epilepsy. In our most recent review, we discuss an overview of epilepsy genetics in 2023, spanning topics of novel methods of gene identification, polygenic mechanisms, new presentations of established genes, and multifaceted efforts of phenotypic characterization. In addition, we discuss the increasingly critical roles of advocacy organizations. Here is a summary of our recent review.

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The pebbles of Demosthenes – stuttering genetics in 2023

Zebra finches. Exactly one year ago, I wrote my last blog post on the genetics of stuttering and thought that it would be time for an update. Here, I would like to explore why stuttering is a truly neglected neurogenetic disorder and why we have made so little progress. In addition, I would like to give a brief update on where we are right now, looking at stuttering from the perspective of the wider pediatric neurogenetics field. In addition, we will unleash the power of EMR genomics to query the medical records of more than 52,000 individuals to find associated genes, and we will discuss a monogenic cause of familial childhood-onset fluency disorders that we did not expect to find. Here is a summary of the last 12 months in stuttering genetics. Continue reading

How precise is precision medicine – the difference between theoretical guidelines and real-world practice in pediatric epilepsy

Precision medicine. This post continues the discussion on how we can make sense of clinical data in the absence of outcomes in the context of precision medicine – a concept that drives much of what we do on a research basis. The fundamental idea is that clinical care in pediatric epilepsies can be personalized and tailored to underlying etiologies. With continual progress in gene curation and variant interpretation alongside clinical knowledge, we typically expect that treatment suggestions are immediately implemented after the discovery of the causative genetic etiology. For example, a child with early onset epileptic encephalopathy is found to have a gain-of-function variant in SCN8A and is almost immediately started on a sodium channel blocker such as Trileptal. However, to what extent is this the case? In the context of precision medicine, how precise are we exactly?

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Why variants of uncertain significance need explanatoriness

ACMG. Imagine the following scenario: you identify a de novo variant in SCN1A in a young child with the typical clinical features of Dravet Syndrome. However, the lab returns the variant as a variant of uncertain significance. The variant is a missense variant that has never been seen before and the lab argues that they are simply applying the current variant classification criteria. Certainly, either the lab is wrong or the variant classification criteria are deficient. Shouldn’t this variant be a pathogenic variant? Your patient clearly has the typical clinical features that are very unlikely explained by anything but the de novo SCN1A variant. In fact, both assumptions are incorrect, but it is important to know the background. Here is a blog post on why variant classification is distinct from assessing whether variants are explanatory in a clinical context. And please allow me to introduce a neologism: explanatoriness. Continue reading

Anatomy, physiology, and the art of motorcycle maintenance

Zen. This weekend, I finished Robert Pirsig’s Zen and the Art of Motorcycle Maintenance. The unfinished task of reading this book has followed me through my entire academic career. It was initially given to me as a gift for being an anatomy tutor in medical school. Independently, I received it as a gift when I passed my German child neurology boards. I started this book several times, but never finished it, and reading this book took me 25 years. As my professor’s thoughts about various approaches to studying medicine have echoed with me since I was a student tutor, this book deserves its own blog post and an enquiry into values (as Pirsig would say) of anatomy versus physiology. Continue reading

CHD2 – here is what you need to know in 2023

Chromodomain. Today is International CHD2 Awareness Day and we are publishing this blog post in time for our CHD2 webinar where we present the result of a four-week sprint to analyze harmonized clinical data. We also updated our gene page on CHD2, which was long overdue. In addition to becoming a more well-known gene, here are three things to know about CHD2 in 2023. Continue reading

Precision medicine in the absence of outcomes

EMR. Genomic data is increasingly available for large patient cohorts. In parallel, healthcare is increasingly digitized and large amounts of data can easily be extracted and analyzed at the click of a button. In principle, this should provide tremendous opportunities to understand how epilepsy care can be personalized based on genetic factors. However, we quickly run into challenges. Obtaining information on seizure frequencies, for example, requires manual chart review. Trying to understand how a person’s genetic makeup affects responses to anti-seizure medications is therefore not possible in large healthcare systems where related questions in other diseases can increasingly be answered. Here is a brief overview of how we can meaningfully engage with clinical data when outcomes are simply not available. Continue reading

SCN1A in FinnGen – epilepsy, dementia, and type 2 diabetes

Isolates. Last week, the FinnGen biobank went live, and Nature dedicated an entire issue to the launch of this initiative. In brief, FinnGen is a large Finnish research project providing genomic and clinical data from a Finnish biobank with the aim to provide new insights into human disease. Finland is an isolated population, which offers unique insights into the role of rare variants in disease. When I checked the FinnGen database for association with SCN1A, I was surprised that three missense variants have been associated with various diseases. Here is what a founder population can tell us about the various roles of SCN1A in human disease. Continue reading

TRPM3 – a heat sensor involved in epileptic encephalopathies

A long-awaited answer. Gene discovery in the epilepsies is continuing, and some novel genetic etiologies are quite surprising given that the particular genes had previously been described in a completely different context. One of these examples is TRPM3. In our recent publication, we further define TRPM3 as a gene causative of a variety of neurodevelopmental disorders. Also notably, we find that the anti-seizure medication primidone can be a helpful treatment in individuals with TRPM3. Beyond outlining the TRPM3 spectrum, our publication helped us find a long-awaited diagnosis for one of our research participants, one that took four years to prove. Here is the TRPM3 story. Continue reading

The history of epilepsy genetics

Timeline. There are a few factors converging at the moment that motivated me to write this blog post. Our blog is officially 14 years old, a fact that has generated surprise, but also nostalgia over the weekend. Second, we were asked to provide an editorial for an interesting review paper by the Lal group, which data-mined PubMed to characterize the history of epilepsy gene discovery. And third, I have heard too often that our 2016 timeline of epilepsy gene discovery that is often used in presentations is antiquated. Let us provide everybody with an update in this blog post. But first, let’s start with a seemingly easy question: what exactly is an epilepsy gene? Continue reading