Epi25 – redefining epilepsy genetics through exomes of 17,000 individuals

The Epi25 study. On August 1, the Epi25 study was published in the American Journal of Human Genetics. Epi25 is the major, international effort to understand the genetics of common and rare epilepsies through exome sequencing, and our current study now presents the first results on what we can see if we look at the genetics of the epilepsies in thousands of individuals, including more than 9,000 persons with epilepsy and 8,000 controls. The Epi25 study finds that individuals with epilepsy carry more ultra-rare, deleterious variants than controls, especially in known or presumed candidate genes. This is a significant finding that tells us about the inner genetic architecture of the epilepsies beyond the role of monogenic causes. However, as with many previous studies at this scale, the first publication merely scratches the surface and provides an enormous amount of data for further studies. Here is a brief summary of the Epi25 study and some of the most prominent genes in the epilepsies that were completely unknown previously. Continue reading

V is for valine – VARS mutations in epileptic encephalopathy

Transfer RNAs. A critical step in translating a cDNA into proteins involves transfer RNAs (tRNAs) that deliver a specific amino acid to the ribosome based on a specific codon in the messenger RNA. Thereby, tRNAs establish the physical link between the mRNA and the amino acid sequence of the growing protein, an essential cellular function. In order for tRNAs to be loaded with the appropriate amino acids, the organism has developed enzymes specific for the individual amino acids that are referred to as tRNA ligases or, more precisely, aminoacyl tRNA synthetases (aaRS). Despite the ubiquitous role of aaRS in the cell, pathogenic variants in genes coding for specific aaRS result primarily in neurological phenotypes, ranging from peripheral neuropathy to early-onset epileptic encephalopathies. In two recent back-to-back publications, bi-allelic pathogenic variants in VARS are described as a novel cause for epileptic encephalopathy, adding VARS to the list of aaRS genes linked to human disease and solving an almost decade-old mystery. Continue reading

E2 – collaborations and lessons learnt

E2. The advent of next generation sequencing allowed unimagined scope for large scale genetic studies. It quickly became clear that whilst new technologies could be used to solve single families, major advances would only occur by collaboration. This led to the formation of a number of Consortia – in the United States EPGP leading onto Epi4K and in Europe EuroEPINOMICS and EpiRES etc as well as a number of smaller consortia. Even with these multicentre collaborations it was clear that “bigger was better”, and attempts were made to try and synergize efforts across continents.  Continue reading

DNM1 encephalopathy – interneurons, endocytosis, and study group

Dynamin 1. De novo mutations in DNM1 coding for Dynamin 1 are increasingly recognized as a cause for epileptic encephalopathies. However, given the role of Dynamin 1 in endocytosis in a large number of cells, the precise mechanisms how mutations may result in seizures are poorly understood. Now two recent publications in PLOS Genetics and Neurology Genetics explore the functional effects of epilepsy-related DNM1 mutations. The publication of both manuscripts is also a timely reminder to announce our international DNM1 study group that has the aim to better understand the phenotype of this disease. Continue reading

How to get started in epilepsy genetics – The Channelopathist’s third birthday

Happy birthday. The Channelopathist turned three last week, i.e. exactly three years ago we started writing regular blog posts on epilepsy and genes, starting with a post on how SCN2A was rediscovered in neurodevelopmental disorders. Since we had many new subscribers last year, I thought that I could use this opportunity to write a brief post on how you can get started on Beyond The Ion Channel and how you can navigate our blog. Continue reading

The three challenges of epilepsy precision medicine

Half Moon Bay. I am on my way back from the Precision Medicine Workshop at Half Moon Bay, realizing again that blog posts from scientific meetings are often boring and difficult to write. However, let me try to put together a few thoughts about this meeting. Basically, there are three challenges for epilepsy genetics in the era of precision medicine. Continue reading

Invitation for the EuroEPINOMICS General Assembly in Tübingen

We need to talk. Much has happened in EuroEPINOMICS land ever since the launch of this Eurocores activity in 2011. Back then, exomes were still a realistic, but somewhat remote possibility and the complexity and ambiguity of the human genome was only beginning to be revealed. Now, roughly two years later, we have witnessed major breakthroughs in understanding epilepsy through genetic findings and we have generated large datasets on common and rare epilepsy syndromes that require an unanticipated effort for data mining and sharing. The EuroEPINOMICS Consortium will hold its 2013 General Assembly in Tübingen, Germany, from 30.10-01.11.2013. This meeting will connect all four Collaborative Research Projects and will be the central meeting of this year to jointly discuss our current activities and plans for the future. Continue reading

Invitation for the 2013 Young Researchers Meeting

This time, the desert. After the successful meeting for Young Researchers in Epileptology in Kiel last year, we would like to invite young and senior researchers in the field for the 2013 meeting, which will take place on December 14th, 2013 in Sde Boker, Israel. This year’s meeting is embedded in a small international meeting from Dec 12th-14th on epilepsy genetics with the primary aim of bringing together researchers from Israel and Palestine. As last year, we would like to extend the invitation for this year’s Young Researchers Meeting in Epileptology to all young scientists involved in the field. Don’t forget to bring water and sunscreen; we’re going to the Negev Desert. 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.

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