GABRB3, 15q dups, and CNVs from exomes

GABAergic. Let’s start out with a provocative statement. There is a single gene that may explain more cases of Lennox-Gastaut Syndrome (LGS) and Infantile Spasms (IS) than you would expect, rivalling SCN1A for the most common gene found in this group of patients. It’s a gene that you are probably aware of but that you may think to be a very rare finding. In a recent publication in Annals of Neurology, the Epi4K consortium published their recent analysis of copy number variations that were derived from exome data. Combining de novo mutations and copy number variations points to GABRB3 as a major player in LGS and IS, explaining probably more than 2% of patients. Let’s find out about the twilight zone, strategies to obtain structural variants from exomes, and the re-emergence of the 15q duplication syndrome. Continue reading

Publications of the week: SCN8A, SYN1, ZDHHC9, and SCNM1

Power outage. This week’s publications of the week were conceptualized in complete darkness. A thunderstorm had hit the Philadelphia area on Tuesday, leading to widespread power outages in the region. I found myself in the strange position of being without power for a night, but with full strength cell phone reception and a completely charged laptop battery. Here is our post on the most relevant publications of the last few weeks, written in the calm of a dark night where the only sound around was the howling of our neighbor’s backup generator. Continue reading

Exomes on the go – adventures with wANNOVAR

Going cloud. This post is about my most recent discovery when I was trying to modernize some of the bioinformatics tools that I had on my laptop. My experience with variant annotation is a good example of the latest trend in bioinformatics: replacing precise, but difficult-to-use tools by web-based convenience – I didn’t need to install anything after all. This is a brief journey into the world of variant annotation, taking advantage of my new favorite tool, wANNOVAR and applying it to the Epi4K dataset. Continue reading

SCN1A and Dravet Syndrome – your questions for the Channelopathist

Comments. After posting our 2015 update on what you should know about SCN1A, we received a number of comments on our blog and by email. We usually have the policy to respond to every comment individually. However, after we had realized that we had fallen behind with a few replies for several weeks, we felt that it might be worthwhile rephrasing some of the questions as general topics to write about, especially since many of your questions raised interesting points. Here are the questions that you asked regarding SCN1A and Dravet Syndrome. Continue reading

Reelin, migration and an unexpected gene for lateral temporal lobe epilepsy

Reeler. In 1951, the geneticist D.S. Falconer identified a spontaneous mouse mutant with an abnormal, “reeling” gait. This mouse, aptly called reeler, was later found to have developmental abnormalities of the cerebellum and, most prominently, an inversion of the layers of the cortex. At this point, interest was piqued to identify the underlying gene, which was eventually pinpointed in 1995. Reelin, the culprit gene, was found to be a secreted protein of cortical support cells and was subsequently found to be the cause of human lissencephaly with cerebellar hypoplasia (LCH). In a recent study in the American Journal of Human Genetics, reelin takes on a new role as a novel gene for a familial form of lateral temporal lobe epilepsy. Continue reading

SCN1A – this is what you should know in 2015

2015 update. Our updates on SCN1A mutations and Dravet Syndrome are amongst our most frequently read posts. Therefore, following the tradition of annual reviews that we started last year, we thought that a quick update on SCN1A would be timely again, building on our previous 2014 update. These are the five things about SCN1A that you should know in 2015. Continue reading

Salt matters – SIK1 in epileptic encephalopathies

Inducible. Next generation sequencing technologies have the tremendous potential to identify disease-causing genes in a hypothesis-free manner. In a recent publication in the American Journal of Human Genetics, mutations in the gene for the salt-inducible kinase 1 (SIK1) are found in patients with early onset epileptic encephalopathy. In addition to a previously unknown functional network related to intracellular salt in the CNS, the authors demonstrate a peculiar mutational mechanism – activating truncation mutations. Continue reading

Launching the Epilepsy Genetics Initiative – Go EGI!

Launch. This week, the Epilepsy Genetics Initiative (EGI) was launched. EGI was founded by Citizens United for Research in Epilepsy (CURE) and represents a large database for diagnostic and research exomes that will guarantee regular re-analysis of exome data, which is particularly relevant for the large number of exomes that we think are negative. Here is a brief blog post why all exomes should eventually find their way into EGI. Continue reading

Identifying the Doose gene – SLC6A1 mutations in Myoclonic Astatic Epilepsy

Doose Syndrome. In the early 1970s, a group of children with severe childhood epilepsies was found to have comparable clinical features that consisted of quick jerks and subsequent drop attacks amongst other types of epileptic seizures. These seizures, myoclonic-astatic or myoclonic-atonic seizures, eventually became the defining feature of an epilepsy syndrome referred to as Myoclonic Astatic Epilepsy or Doose Syndrome. In the recent issue of the American Journal of Human Genetics, we report on the first true gene for Doose Syndrome. Here is the story of SLC6A1 (GAT-1). Continue reading

Epi25 – breaking the genetic sound barrier

25,000 genomes. The epilepsy community is currently preparing for the largest sequencing project in the epilepsies so far, responding to a call by the National Human Genome Research Institute (NHGRI). If funded, the Epi25 project will allow us to begin sequencing 25,000 individuals with epilepsy, helping us to achieve the next, necessary level for gene discovery in human epilepsies. Here are some of the reasons why we need Epi25 and why you should be part of it. Continue reading