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

These are the genes we don’t need – or do we?

Rare human knockouts. Recessive disorders arise when both copies of a causative gene are affected by mutations. These diseases are thought to be a very rare occurrence, but the cumulative impact of these conditions is not known. Population genome sequencing offers the possibility to assess the spectrum and distribution of potentially causative mutations in large groups of individuals. In a recent publication from deCODE published in Nature Genetics, the authors examine the population spectrum of rare human knockouts using the unique genetic data and population structure of the Icelanders. Here is the story about potential candidate genes identified by population genetics. Continue reading

Cause or coincidence – recessive SCN1A variants in Dravet Syndrome

Recessive epilepsies. Dravet Syndrome is one of the most prominent genetic epilepsies and presents in the first year of life with prolonged fever-associated seizures. Haploinsufficiency of SCN1A, either through mutations or deletions, is the major cause of Dravet Syndrome. In a recent publication in the European Journal of Pediatric Neurology, two families with recessive Dravet Syndrome and biallelic SCN1A variants are reported. Let’s have a look at how to interpret these findings. Continue reading

USP9X, Ubiquitin, and the PRICKLE interactome

PRICKLE. There are some genes implicated in human epilepsies that we have a hard time making sense of. PRICKLE1, implicated in a recessive progressive myoclonus epilepsy, is one of these genes. In a recent publication in PLoS Genetics, the interactome of the enigmatic PRICKLE proteins is explored. The authors rediscover an almost forgotten gene implicated in intellectual disability. Continue reading

The two faces of KCNA2 – a novel epileptic encephalopathy

Delayed rectifier. The discovery of de novo mutations in ion channel genes as a cause for genetic epilepsies continues. In a recent publication in Nature Genetics, we have identified de novo mutations in KCNA2 as a novel cause of epileptic encephalopathies associated with ataxia. Interestingly, even within a single gene, two different phenotypes seem to be emerging. Continue reading

Beyond SCN1A – Copy Number Variations in fever-associated epilepsies

Fever and epilepsy. When it comes to epilepsy and fever, either Febrile Seizures or Dravet Syndrome are usually the most prominent topics on our blog. However, in addition to these syndromes, there various other epilepsies that have fever-related seizures as a prominent feature. In a recent publication in Epilepsia, we investigated the role of microdeletions in a group of patients with prominent fever-associated epilepsies. Our findings suggest that fever-associated epilepsy syndromes may be a presentation of known microdeletion syndromes. Continue reading

Speech dyspraxia and dysarthria – the other side of GRIN2A

GRIN2A. Mutations in several genes coding for NMDA receptor subunits have recently been found in various neurodevelopmental disorders. Amongst the different genes, GRIN2A is one of the most prominent ones and mutations in this gene are found in patients with epilepsy-aphasia syndromes. So far, we have mainly looked at GRIN2A from the epilepsy side. In a recent publication in Neurology, Turner and collaborators now examine the speech phenotype in GRIN2A families. They examine two families where speech issues are a prominent phenotypic feature. It turns out that GRIN2A mutations may predispose to a distinct speech phenotype. Continue reading

Publications of the week – CNTNAP2, DEPDC5, and autism whole-genome sequencing

Issue 4/2015. Trying to keep up with the publications of the week in the field, we have selected three manuscripts this week, which challenge some of our well-established beliefs. It’s about an autism gene losing its statistical support, a familial epilepsy gene rediscovered in focal cortical dysplasia, and the surprises of whole-genome sequencing in familial autism. Continue reading