Story of a genetic shape-shifter: SCN2A in benign seizures, autism and epileptic encephalopathy

The other sodium channel gene. The week before Christmas, the Kiel group identified its first patient with SCN2A encephalopathy. At the same time, a questionably benign SNP in the same gene is haunting our Israel Epilepsy Family Project. Time to review the mysterious SCN2A gene that initially entered the scene as a candidate for a rare, benign familial epilepsy syndrome – only to return as one of the most prominent genes for autism, intellectual disability, and epileptic encephalopathies to date. 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

Epileptic encephalopathies: de novo mutations take center stage

The de novo paradigm. De novo mutations play a significant role in many neurodevelopmental disorders including autism, intellectual disability and schizophrenia. In addition, several smaller studies have indicated a role for de novo mutations in severe epilepsies. However, unless known genes for human epilepsies are involved, findings from large-scale genetic studies are difficult to interpret. De novo mutations are also seen in unaffected individuals and only very few genes are observed more than once. Now, a publication in Nature by the Epi4K and EPGP collaborators uses a novel framework to tell pathogenic mutations from genomic noise. Their study provides very strong evidence for a predominant role of de novo mutations in Infantile Spasms and Lennox-Gastaut Syndrome. 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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De novo mutations in Infantile Spasms and Lennox-Gastaut Syndrome

Quantum leap. At the Annual Meeting of the American Epilepsy Society, the Epi4K consortium presented the first data on exome sequencing in epileptic encephalopathies. This data is the most exciting finding in the field of epilepsy genetics in 2012 so far, as it provides a deep insight into the genetic architecture of Infantile Spasms (IS) and Lennox-Gastaut Syndrome (LGS). With the findings presented by the Epi4K collaborators, the epileptic encephalopathies are joining a group of neurodevelopmental disorders with a significant burden of de novo mutations.  However, there are important differences that set both IS and LGS apart from diseases like autism, intellectual disability and schizophrenia. Continue reading

CASK aberrations in Ohtahara syndrome

Suppression-burst. Ohtahara Syndrome is a rare epileptic encephalopathy with onset in the first weeks of life. The typical EEG feature of Ohtahara Syndrome is suppression-burst activity, suggesting a profound disruption of cerebral function. Ohtahara Syndrome can be caused by severe brain malformations and neurometabolic disorders. In addition, mutations in ARX and STXBP1 are known causes of Ohtahara Syndrome. In a recent publication in Epilepsia, genetic alterations in CASK were identified in patients with Ohtahara Syndrome and cerebellar hypoplasia. Given that CASK mutations are the known cause for a complex X-chromosomal disorder, this report provides us with an interesting example of what happens when genes underlying distinct clinical dysmorphology syndromes cross over to the epilepsies. Continue reading

Exome sequencing in epileptic encephalopathies – the powers that be

The power, over and over again. I must admit that I am thoroughly confused by power calculations for rare genetic variants, particularly for de novo variants that are identified through trio exome sequencing. Carolien has recently written a post about the results we can expect from exome sequencing studies. For a current grant proposal, I have now tried to estimate the rate of de novos using a small simulation experiment. And I have realized that we need to re-think the concept of power. Continue reading

Traveling with Lennox – myoclonic jerks, West Syndrome and the 34th meridian

Where is West Syndrome? Earlier this week while browsing through the contents of Lennox’s book, I wondered where his description of West Syndrome was hidden. Lennox is very careful in reviewing the historical data on epilepsy, but for some reason, he did not mention the report by William James West, who described a particular type of epilepsy in his own son that would later be named after him. Then, when I had almost forgotten that I was on the lookout for West Syndrome, I stumbled upon it in the chapter on myoclonic seizures. Continue reading