25,000 genomes. The epilepsy community is currently preparing for the largest sequencing project in the epilepsies so far, responding to a call by the National Human Genome Research Institute (NHGRI). If funded, the Epi25 project will allow us to begin sequencing 25,000 individuals with epilepsy, helping us to achieve the next, necessary level for gene discovery in human epilepsies. Here are some of the reasons why we need Epi25 and why you should be part of it. Continue reading
Tag Archives: genetic architecture
How to find recessive disease genes for epileptic encephalopathies
The E2 story continues. There has been major progress in identifying the role of de novo mutations in infantile spasms and other epileptic encephalopathies. Over the last two years, more than 20 new genes for epileptic encephalopathies were discovered and we have good evidence suggesting that de novo mutations play a major role in these disorders. Moreover, we have gotten a good sense on how complicated it can be to call a de novo mutation pathogenic given the flood of rare genetic variants in the human genome. However, de novo mutations are not what we think about clinically when assessing a patient with new-onset epileptic encephalopathy. In a clinical setting, we are often concerned about underlying metabolic disorders, many of which are recessive. Accordingly, we felt that the next task of the E2 consortium was to assess the role of inherited variants in epileptic encephalopathies. Just to tell you in advance, it is not as easy as it sounds.
Should we stop talking about heritability in 2014?
Genetic epidemiology. Long before the first epilepsy gene was discovered, clinicians and researchers were wondering about a genetic contribution to epilepsy. Some epilepsy syndrome were found to run in families in an autosomal dominant or recessive pattern. In other epilepsies, there was an obvious excess of affected family members in the immediate or extended family. And this is how we got stuck with the concept of heritability. Let’s review the perils and pitfalls of heritability and ask the question whether we should retire this concept in the current era of genomic medicine. Continue reading
This is what you will see in epilepsy genetics in the next five years
Welcome to our new blog. We have moved our blog to a new server, and this is the first post on our new platform. Let’s start out this new era with a general overview of what will happen in the field of epilepsy genetics in the next five years. We definitely plan to follow the developments as we did over the last two years. Here are the six things that we will look back upon in five years. Continue reading
Living in a post-linkage world, craving knowledge
Genomics meets linkage. This blog post is about family studies in epilepsy genetics. One of my tasks for the next two months is to write the “Trilateral Grant” – we were invited to submit a full proposal for a German-Israeli-Palestinian grant by the German Research Foundation (DFG) on the genetics of familial epilepsies. As keeping up our blogging schedule will be my other big task for the coming months, I thought that I could combine both and explore some topics regarding family studies on this blog. Let’s start with a sobering fact – small dominant families remain difficult to solve, not because of too little but rather too much genetic data. 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.
Navigating the epilepsiome – live from Tübingen
2D. I am writing this post during our EuroEPINOMICS meeting in Tübingen listening to presentation from CoGIE, the EuroEPINOMICS project working on IGE/GGE and Rolandic Epilepsies and RES, the project on rare epilepsies. At some point during the afternoon, I made my selection for the best graph during the presentations today – an overview of the conservation space of epilepsy genes. Continue reading
G proteins, GNAO1 mutations and Ohtahara Syndrome
G proteins. Intracellular signaling in neurons can occur through various mechanisms including so-called second messengers. G proteins constitute an important part of the signaling cascade that translates the signal from membrane-bound receptors. On neurons, GABA-B receptors or alpha-2 adrenergic receptors use signal transduction through the so-called G alpha-o proteins, which are particularly abundant in the CNS and encoded by the GNAO1 gene. Now a recent paper in the American Journal of Human Genetics describes de novo mutations in Ohtahara Syndrome and movement disorders. Continue reading
Reinventing a consortium – the RES data sharing policy
Share or be shared. During the last two weeks, the RES consortium has approved a new data sharing policy that will allow us to work with increased transparency and accountability within our upcoming projects. This new data sharing policy is a consequent extension of the previous protocols we had in earlier consortia – with one major difference. This time, it’s in writing. While we are getting ready to tackle the large dataset on epileptic encephalopathies released by the Sanger Institute, we took a moment to talk about how things should be running.
16p13.11 microdeletions and the male bias
The enigmatic deletion. Amongst the various microdeletions implicated in human epilepsy, the 16q13.11 microdeletion is one of the structural variations that poses significant difficulties in understanding its associated risk and phenotypes. Now a recent paper in PLOS One investigates a large cohort of patients with various neurodevelopmental disorders for microdeletions in the 16p13.11 region. And particularly the finding regarding the sex distribution of symptomatic deletion carriers is remarkable. Continue reading