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
Tag Archives: exome sequencing
Looking back at 2012 – The year in epilepsy genetics
Concluding remarks. 2012 was an exciting year in epilepsy genetics with many surprises in the field. During this final post of this year, we would like to look back at our posts of the year, summarizing the post that received the most attention and also summarizing the posts that we didn’t write. 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
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
Missed SCN1A mutations in Dravet Syndrome – a matter of degrees
Back from AES. I have just come back from the 66th Annual Meeting of the American Epilepsy Society and I would like to share some of the most recent findings that were presented at this meeting. Since we felt that our presentation on the “re-discovery” of SCN1A mutations in SCN1A-negative patients with Dravet Syndrome received quite some attention, I thought that I would share this part of our presentation as a brief screencast. In particular, I would like to thank Anna-Kaisa Anttonen and Anna-Elina Lehesjoki for providing us with the trace files. And of course thanks to everybody in RES who was involved in this.
The RES-experiments: what results can be expected
Now the experiments to find de novo variants for epileptic encephalopathies within the Euroepinomics RES-project are well underway and first data are coming out, it is a good moment to pause and think about what results we can expect, and how these should be interpreted. For this it is very nice that recent large experiments in autism have provided so much useful data. In this post, I will explore what we can expect in experiments in which we perform whole exome sequencing in a group of patients and their parents to identify de novo variants that could be the cause of the disorder.
The exome fallacy
Are you fully covered? My experience with a phenomenon I shall call exome fallacy began in 2011. While browsing the exomes of a few patients with epileptic encephalopathies, we wanted to have a quick look at whether we could exclude mutations in the epilepsy gene SCN1A in our patients through exome data. As some of you might already guess, the words “exome” and “exclude” don’t go well together and we learned the hard way that each individual exome covers certain parts of the gene quite well. However, if you expect your exome data to have sufficient quality to cover an entire gene in several individuals, you end up disappointed. But there is even more to the exome fallacy than you might think… Continue reading
Exomes to the extreme to identify modifier gene in cystic fibrosis
Monogenic modifiers. Exome sequencing is a well established method to find causative genes in monogenic disorders, with probably more than 100 genes identified through this method in the last two years. In contrast to the ever-expanding list of monogenic diseases solved through massive parallel sequencing, there is widespread skepticism regarding its usefulness in complex genetic disorders. Now, a recent study in Nature Genetics suggests another application for exome sequencing, the identification of modifier genes in monogenic disorders. Continue reading
ATP1A3 links alternating hemiplegia of childhood with genetic dystonia and parkinsonism
Alternating Hemiplegia of Childhood (AHC). Acute hemiplegia in children, i.e. weakness of one side of the body, is always a medical emergency. Causes for a sudden hemiplegia can include intracranial bleeds, tumors and rare metabolic disorders. Immediate diagnostic work-up is paramount. In some children, no cause can be found on brain imaging and extensive testing, and the episode remits after hours or days. Strangely, during a following episode, the other side of the body is affected. This condition has been named Alternating Hemiplegia of Childhood (AHC) by Verret and Steele in 1971. AHC is an enigmatic disorder, which is sometimes associated with epilepsy, developmental delay and dystonia. Even though some cases with mutations in SCN1A, CACNA1A, and ATP1A2 have reported, most cases of AHC are unresolved. Given some resemblance with epilepsy and familial hemiplegic migraine, many children with AHC are followed up by epileptologists. The major cause of AHC has now been identified in a recent study… Continue reading
The heritability of schizophrenia, as told by common SNPs
Heritability 2.0. Genome-wide association studies (GWAS) have acquired a slightly negative connotation in the last two years as the results of the enormous efforts were moderate at best. Even though several hundreds of variants have been identified as susceptibility genes for various diseases, the identified genetic risk factors only explain a tiny fraction of the risk for these diseases. Much of what causes common and rare diseases is still unknown – there is a vast discrepancy between population estimates of the genetic contribution and the contribution explained through identified genetic risk factors. This phenomenon has been labeled the “missing heritability”. Now, a recent study using novel statistical tools for GWAS data finds that there is not that much missing after all… Continue reading
