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
Tag Archives: Dravet
How SCN1A comes to its own rescue
Modifier genes. When I compiled the most important updates on SCN1A genetics a few weeks ago, I forgot one of the most unusual studies that makes you pause and think. To provide some background: ever since the initial discovery of familial epilepsy syndromes such as Genetic Epilepsy with Febrile Seizures Plus (GEFS+), the intrafamilial range of presentations has been a big mystery. Within single families, we typically observe a very broad spectrum of phenotypes. Furthermore, in some families, the range of phenotypes is extreme – the same SCN1A variant may cause Dravet Syndrome in one individual, while other individuals are unaffected. In a recent study, we stumbled upon an unusual cause for this variability: a second SCN1A variant that neutralizes the pathogenic effect of the familial variant. Here is a summary of this unusual story. Continue reading
Why I am still struggling with SCN9A in Dravet Syndrome
Susceptibility. Two weeks ago, we published a post on rare variants in SCN9A as potential susceptibility genes for Dravet Syndrome with mutations in SCN1A. Ever since reading the article by Mulley and collaborators, I had tried to come up with an idea of what the genetic architecture might look like if both de novo variants and inherited variants contribute. I wanted to follow up on my earlier post with this brief back-of-the-envelope calculation. Continue reading
The children of the genomic revolution
Invitation for the Young Investigators workshop in Kiel, August 23rd-25th, 2012
The workshop. We would like to invite all young scientists within the EuroEPINOMICS program for a joint workshop on pediatric epileptology in late August this year. As a spin-off of the EuroEPINOMICS program, we successfully acquired funding for this workshop through the Hamburg Academy of Science. The idea behind this workshop is to bring together young clinicians and researchers working in the field of pediatric epileptology for an intensive exchange of experiences and knowledge. Researchers from different areas will have the chance to meet and learn from each other and to initiate new collaborations and networks.
The sun is setting over the Mornington Peninsula, Australia. Much of the genetic architecture of the epilepsies is still an unknown terra australis that needs young researchers to understand it.
Preliminary Program. We are planning to have talks by young researchers who will present a broad overview and provide insights into recent discoveries on the genetic causes of pediatric epilepsies, the pathophysiological mechanisms and the clinical relevance. Keynote lectures by experienced scientists including Olivier Dulac (“Is pediatric epilepsy research beneficial?”) and Kristien Hens (“Ethical issues in paediatric epilepsy research“) will provide an interesting framework for this meeting. Additionally, all participants may present their current research projects and critically discuss them with their peers. Following this full work program, we will enjoy the summer evenings at the Baltic Sea in Kiel. Here you will find the links to the flyer and the preliminary program for the workshop.
Travel support is granted. We will support participants with the travel expenses and this meeting is without a registration fee thanks to the support of the Academy of Science, University of Kiel and other sponsors. For more information visit our website or contact us on YoungResearchers@epilepsiegenetik.de.
We are looking forward to seeing you in Kiel in August. Don’t miss it!
Next Generation Sequencing as a diagnostic tool in the epilepsy clinic
Remember Guthrie cards and the heel stick for newborn screening? It will be a thing of the past in 10 years replaced by methods performed through Next Generation Sequencing (NGS). NHGRI and NICHD have already committed to a $25M program for Next Generation Sequencing in Newborn Screening and first reports appear describing the value of exome sequencing in solving undiagnosed cases. However, these reports all leave clinicians working in the epilepsy clinic scratching their heads – this all sounds very good, but what can you offer your patients already, not just in 2-3 years?
265 genes at once. A team led by the EuroEPINOMICS researchers Johannes Lemke and Saskia Biskup has now evaluated the feasibility of targeted Next Generation Sequencing of a panel of epilepsy genes and the results published in Epilepsia last week are quite impressive. With their panel of 265 genes, they identified mutations in 16/33 patients with unclassified, presumably genetic epilepsy. While the overall yield of this candidate panel is probably lower than the impressive 50% in their pioneer study, these results clearly show that the general workflow in the epilepsy clinic is ready to shift from candidate gene screening to Next Gen panel analysis.
New and old genes identified. The list of genes identified in their screening is a mixed bag of epilepsy genes, many of which were identified in syndromes with a high degree of clinical suspicion including mutations in SCN1A, SCN2A and KCNQ3. Interestingly, some unlikely candidates also popped up. One patient with a clinical picture of Dravet Syndrome (DS) had a mutation in TPP1, the gene causative for Neuronal Ceroid Lipofuscinosis Type 2. This unexpected finding highlights another important “side-effect” of NGS: we will probably discover many unusual phenotypes for known disorders.
You wouldn’t think so, but panels are sometimes more thorough. Lemke and coworkers identify mutations in SCN1A in three patients with DS. This alone would not be all that remarkable. However, these three patients were previously reported to be negative for SCN1A by Sanger sequencing. This phenomenon is not new. In addition to identifying GABRA1 in SCN1A-negative DS, Mefford and colleagues also identified a mutation in SCN1A by exome in a patient with DS that was missed by conventional sequencing. While it is difficult to compare exome and conventional sequencing, these two anectodes at least suggest that NGS is not fairing any worse than conventional methods.
Study by Lemke et al. demonstrating the usefulness of targeted NGS in patients with epilepsy. Unlike few other genetic technologies, targeted NGS is very likely to alter your work flow in clinic at short term.
Targeted sequencing vs. exome. In the upcoming 12-24 months, we expect an intense debate on whether targeted sequencing is actually necessary or whether you could directly apply diagnostic exome sequencing. Targeted technologies – for now – have the advantage of the higher coverage, i.e. the eventual quality and completeness of candidate gene sequences higher than in exome studies. However, the field is evolving and the next, better technology might already be around the corner.
