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
Tag Archives: whole exome sequencing
Traveling beyond the ion channel
A how-to guide. July is going to be a slow month for the EuroEPINOMICS blog. Both Roland and I are going on vacation and we will use this time to migrate the entire blog to a more stable and supported server environment. While this always sounds like a quick thing to do, it involves much testing, experimenting and debating and that’s why the Channelopathist will be closed for the month of July. However, we wanted to use this time to provide our readers with brief instructions on how to navigate this blog and our past entries. Speaking of vacation, how far have you traveled beyond the ion channel? 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.
Transmission of rare variants in parent-offspring trios – power or no power?
My untested assumption. Recently, I have boasted quite a bit about the power of the trio design, i.e. the inclusion of patients and parents in the analysis of rare genetic variants. Rare variants, in contrast to monogenic variants that arise de novo, are usually transmitted from unaffected parents and are the big unknown of modern day genetic studies. Much of the missing heritability may be accounted for by rare variants, but identifying these variants from genomic noise is difficult. Power calculations for association studies usually suggest that thousands, if not tens of thousands, of patients are necessary to identify these variants with sufficient statistical certainty, a sample size that the field of epilepsy research may never arrive at. So what about switching to parent-offspring trios? Would this help us? Follow me on a brief statistical journey through the land of rare variants. Continue reading
ST3GAL3 and exome sequencing in autosomal recessive West Syndrome
Autosomal recessive West Syndrome. Exome sequencing and other high-throughput sequencing technologies work best in the identification of recessive disorders. While many cases of West Syndrome are thought to be the result of de novo mutations, recessive inheritance is seen in a subset of patients. In a recent paper in Epilepsia, Edvardson and colleagues now report mutations in ST3GAL3 in a consanguineous Palestinian family with four affected individuals with West Syndrome. This report takes us deep into the chromosomal anatomy of the linkage region, raising the question at what point we can claim that a gene is found. Continue reading
How a pathogenic de novo mutation in SCN1A ended up in the Exome Variant Server
The omics flood. Large amounts of sequence data are produced every day and we can use the genetic information of several thousand individuals as controls of any present-day genetic study. However, much of research on “traditional” epilepsy genes had been performed prior to the genomic era and often only included limited control cohorts. This begs the question whether a closer look at the currently available data might provide additional information. Now, a recent paper in the Journal of Neurogenetics investigates the presence of reported mutations for epilepsy in large, available datasets. And the results are surprising. Continue reading
CNTN2 mutations and autosomal recessive cortical myoclonic tremor with epilepsy
Epilepsy & Tremor. The familial occurrence of epileptic seizures and chronic, non-progressive myoclonic tremor represents a peculiar genetic epilepsy syndrome for which the gene still remains elusive. Several families have been reported with autosomal dominant inheritance, and linkage to chromosomes 2, 5 and 8 have been reported. Now, the story regarding this familial syndrome gets even more enigmatic. In a recent paper in Brain, Stogmann and collaborators identify CNTN2 as the causative gene for a recessive form of cortical myoclonic tremor with epilepsy. 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
Spooky, scary, phantom heritability
Twilight zone. Admittedly, Halloween is already a few weeks behind us, but I was reminded of it a week ago when I stumbled across the concept of phantom heritability. And guess what, this concept has already been out there since early 2012 and, scarily enough, we didn’t notice it. So what is this mysterious conspiracy behind phantom heritability? Well, it’s about things out there beyond our understanding and the fact that we might already know more than we think we know. But be warned, if you decide to read this post, your understanding of genetic architecture might be changed forever. And there is no going back. Boo! Continue reading
A new twist on an old gene: EFHC1 in epileptic encephalopathy
A peculiar gene. There is one gene in the small world of epilepsy genetics that has always troubled me. A gene that has an unknown function and is not expressed in the postnatal brain, but is well established as one of the few genes for autosomal dominant Juvenile Myoclonic Epilepsy (JME). This gene is EFHC1. Now, a recent paper in Epilepsia reports EFHC1 as a possible candidate gene in autosomal recessive epileptic encephalopathy with neonatal onset. The mystery surrounding this gene continues. Continue reading
