Three reasons why we need a new genetic literacy to understand epilepsy

ILAE Genetic Commission weekly. As you might already know, Beyond the Ion Channel has become the official blog of the Genetics Commission of the International League Against Epilepsy. Starting with this post, we would like to publish a weekly post about the issues relevant to what the ILAE-GC does. We’ll kick off this new segment by telling you about the reasons behind the Genetic Literacy Series that is currently in the works. This series of 10 papers will appear this year and next in Epilepsia. Continue reading

Popper, Kuhn, and the paradigm shifts of the genomic revolution

Paradigm shifts no more. During our bioinformatics workshop in Leuven, Roland pointed out that I tend to use the phrase “paradigm shift” too liberally. In fact, the concept of paradigm changes in science was made popular by Thomas Kuhn, an American physicist, historian, and philosopher of science. Kuhn believed that scientists work within a given set of paradigms and believes that they don’t really question them – until everything falls apart. Let me take you on a brief journey through the philosophy of genomics starting with Kuhn’s nemesis, Karl Popper. Continue reading

The genetic architecture toolkit – modeling polygenic disease with rare variants

Architecture. Even though we often write about novel gene findings in the epilepsies, we assume that most epilepsies are complex genetic or polygenic. Polygenic inheritance suggests the genetic architecture is composed of multiple interacting genetic risk factors, each contributing a small proportion to the disease risk. However, when using the phrase genetic architecture, sometimes I am not quite sure what I actually mean by this. For example, how many genes are needed? This is why I wanted to build a model genetic architecture and explore what happens if we build a genetic disease solely from rare risk variants. Follow me to a brief back-of-the-envelope calculation of how this might work.

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Treatable causes of intellectual disability and epilepsy that you don’t want to miss

Think metabolic. We have discussed de novo mutations as a cause of epileptic encephalopathies repeatedly on our blog. While there is emerging evidence that de novo mutations in established genes such as SCN1A or CDKL5 or novel genes including GNAO1 or CHD2 are a major cause of genetic morbidity in patients with epileptic encephalopathies, investigations for de novo mutations are not the immediate knee-jerk reaction in clinical practice. In fact, if a child presents with an epileptic encephalopathy, excluding inborn errors of metabolism (IEM) takes priority. While metabolic causes of epileptic encephalopathies are rare, they need to be excluded as some of these conditions are treatable. In a recent review in Molecular Genetics and Metabolism, van Karnebeek and colleagues review the 89 causes of intellectual disability that are potentially treatable. Many of these conditions also present with epilepsy. They present an updated diagnostic algorithm and provide an online resource for these conditions – in a nutshell, there is an app for that.  Continue reading

A PhD in genomics – lessons learned

This is it! With finishing my PhD I have become an “adult” member of the scientific Graduierungcommunity. I grew out of a bachelor in biochemistry on transfection methods in neuronal cell lines, a research semester in Canberra with focus on B-cell immunology and master into a  PhD in epilepsy genomics. I was involved in the EPICURE IGE copy number projects and recently my work changed to the analysis of rare variants in RE and IGE in the EUROepinomics framework. During this time I was involved in the identification of variants in RBFOX genes and GRIN2A as well as other risk factors which are currently in review. I share my experience and thoughts and hope they help others who are about to or have just started their thesis. The aspects reflect my personal view and some are specific for graduation in disease genomics. Continue reading

Modifier genes in Dravet Syndrome: where to look and how to find them

Converging thoughts. During late 2013, I had several unrelated discussions about the possible role of genetic modifiers of SCN1A in Dravet Syndrome. To some extent, SCN1A is a paradox. One the one hand, the connection between Dravet Syndrome and SCN1A is one of the clearest connections between gene and disease that we see in genetic epilepsies. On the other hand, we see a remarkable phenotypic heterogeneity in families, and some presumably pathogenic SCN1A variants can also be identified in unaffected control individuals. This leaves us with the question whether there are genetic modifiers in Dravet Syndrome that might help provide some insight into additional mechanisms of disease. This post is a collection of 10 individual thoughts that emerged during the discussions last year. Continue reading

Infantile Spasms/Lennox-Gastaut genetics goes transatlantic

Joining forces. The EuroEPINOMICS-RES consortium and Epi4K/EPGP are currently joining forces for genetic studies on epileptic encephalopathies. A first collaborative study focuses on de novo mutations in Infantile Spasms and Lennox-Gastaut-Syndrome. In the last two years, after decades of disappointment, we have finally managed to accomplish a breakthrough in understanding the genetic basis of epileptic encephalopathies. The method of trio-based exome sequencing works amazingly well to identify the genetic cause, and the field currently has the crucial momentum to reach the next level of research. Let’s briefly review why we need international collaborations to disentangle the genetic architecture of the epileptic encephalopathies. Continue reading

From unaffected to Dravet Syndrome – extreme SCN1A phenotypes in a large GEFS+ family

The two faces of SCN1A. Even though the range of phenotypes associated with mutations in SCN1A can be conceptualized as a continuum, there are usually two distinct entities in clinical practice: the severe, epileptic encephalopathy of Dravet Syndrome due to de novo mutations and the usually mild fever-related epilepsies in autosomal dominant GEFS+ families. While Dravet Syndrome can also be seen in some families with Genetic Epilepsy with Febrile Seizures Plus (GEFS+), this is a rare phenomenon; there is usually little overlap between Dravet Syndrome and GEFS+. Within the Israel Epilepsy Family Project, we came across such a family with overlapping phenotypes. This recently published large GEFS+ family probably has the widest phenotypic range reported to date. Continue reading

“Dark social” or “Who is afraid of email?”

Heathrow. Dark social? Threat? I’ll get back to that. I am writing this wrap-up post for the SpotOn 2013 meeting overlooking the British Airways planes on their way to take-off. In the last two days, we caught a glimpse of what online science communication is about. On Saturday, we had our own session #solo13blogs on using blogs for peer-to-peer science communication. As a science communication newbie, I am happy that our session was well received and stimulated quite some discussion. I have taken away three things from this meeting – a new understanding of our readership, an appreciation for Open Access and data sharing, and finally, a fear of the destructive power of dark social that also applies to epilepsy genetics research. But first things first. Continue reading