The sequester and biomedical research – lessons for Europe

Transatlantic. The so-called sequester, automatic spending cuts across the board- have gone into effect in the US and also impact on the level of public funding for biomedical research. In a recent commentary in JAMA, Ezekiel Emmanuel comments on the decline of support for the NIH, which he believes goes far beyond the results of the spending cuts and can be traced back to four main factors. In this post, we would like to discuss to what extent his four main arguments also apply to the European scientific community. Continue reading

FS and FS+ are two distinct diseases, as suggested by twins

GEFS+ reloaded. The genetics of Febrile Seizures (FS) is one big mystery. Even though large families have been reported and multiple linkage studies have been performed, no single susceptibility gene for Febrile Seizures is known. This is somehow surprising, given that FS is by far the most common epilepsy syndrome. In contrast to common FS, genetic research has been very successful in families with Genetic Epilepsy with Febrile Seizures Plus (GEFS+), where Febrile Seizures Plus (FS+) are the most striking feature in families.  Ever since the definition of the GEFS+ spectrum was established, the distinction from common FS has been a matter of debate. Now a twin study in Epilepsy Research suggests FS and FS+ might actually be two very distinct diseases with little genetic overlap. Continue reading

Familial Partial Epilepsy with Variable Foci and mutations in DEPDC5

A long story, a complicated phenotype. Massive parallel sequencing technologies were an innovation in neurogenetics and made the discovery of many genes underlying familial epilepsies possible. However, some epilepsy syndromes turned out to be more “stubborn” than others. Now, in a back-to-back submission in Nature Genetics, two groups report on the gene underlying Familial Partial Epilepsy with Variable Foci (FPEVF). And no, it’s not an ion channel this time. Continue reading

Axiomatic – identifying a novel epilepsy gene that was hidden right before your eyes

The Hague, winter of 1997. Last week challenged my most basic beliefs, which reminded me of “Axiomatic”, a collection of science fiction short stories by Greg Egan. While on holiday in the Netherlands in 1997, I had bought this book in the Den Haag Centraal bookstore, and subsequently lost it or gave it away. I only remembered the title three weeks ago, and ordered it online. The book arrived at the same time that news from Antwerp twisted my brain. In the signature story of “Axiomatic” with the same title, a man acquires a nano-robot based implant that allows him to change his innermost convictions (I told you that it’s science fiction, right?). He basically wants to have the courage to kill the man who murdered his wife. After carrying out his revenge and after the effect of the axiomatic implant has worn off, he starts craving for more, since he is missing the certainty in his life that the implant had given him. I needed to adjust my deeply held expectation on how to find de novo mutations after Tania, a PhD student in the Antwerp lab, had pulled out a de novo mutation in one of our trios that Denovogear had missed. This mutation turned out to be another hit in a gene that we had seen before. Continue reading

Pushing the button for the next exome sequencing round

Galvanize. Last week, the EuroEPINOMICS RES working groups made the final decisions for the selection of trios for exome sequencing at the Sanger Centre, funded jointly by the Sanger Programme on paroxysmal neurological disorders and the EuroEpinomics RES fund. We pushed the button for 102 patient-parent trios to be sequenced. And for some reason, I caught myself humming “Galvanize“, the 2005 big beat hymn by the Chemical Brothers. Continue reading

How to detect de novo mutations in exome data

Taking things apart. Looking for de novo variants using trio exome sequencing is a powerful technique to identify disease-related genes. After having introduced samtools during the last post, this will be post 2/3 in a series on how to perform an analysis of exome data for de novo variants. This time, I would like to take apart the methods that take us from Gigabyte BAM files to small tables with likely variants. So buckle up. Continue reading

The return of TBC1D24

First of its kind. In 2010, a virtually unknown gene became the first epilepsy gene to be discovered through massive parallel sequencing techniques. This gene, TBC1D24, was found in two recessive families with different types of epilepsy. Afterwards, it became silent around this gene with no further findings. Now, a recent paper reports on a third family with a mutation in this gene with a complex phenotype of epileptic encephalopathy and movement disorders. As the mutation is located in an alternative exon of this gene, this raises important issues on how we identify and interpret mutations. Continue reading

Recessive mutations in autism – the return of hidden metabolic disorders

My wrong guesses of 2012. Two weeks ago during a presentation, I had to admit that there is little evidence for a large contribution of recessive or compound heterozygous mutations in epileptic encephalopathies. At the beginning of 2012, I had initially suggested that recessive or compound heterozygous mutation of known neurometabolic disorders could be identified through exome sequencing in sporadic epileptic encephalopathies. However, as of 2013, there is little evidence for this in our data or the data from other consortia. Now, two papers in Cell suggest a significant contribution of recessive mutations in autism including a revival of the “hidden neurometabolic hypothesis”. Continue reading

Red Johanna Day – The signal and the noise

Predictions. December 17th is the day that I consider my annual anniversary in epilepsy genetics. Exactly eight years ago, I was still a student in my final med school year and went to Australia for a job interview. We took a road trip over the weekend and on the evening of the 17th, I was reading Nigel Tan’s review on epilepsy genes aptly entitled The truth is out there while sitting in a rock pool at Red Johanna Beach, a surfing beach at the Great Ocean Road south of Melbourne. Looking back, I think this was one of the few publications that helped me make sense of all the literature on epilepsy association studies. I thought that I would like to be able to write something like this while shivering in the waters of the Bass Strait that are always a little bit too cool. Today, sitting in the cozy warmth of our apartment in Kiel, I have finished reading Nate Silver’s book The Signal and the Noise, a book about making sense of data and predictions. Eight years later, are we any closer to the truth that is out there? Continue reading