EuroEPINOMICS and the golden age of epilepsy gene discovery

Exome era. When a consortium disappears, where does it go and what does it leave behind? I realized last week that exactly 10 years ago, the EuroEPINOMICS Rare Epilepsy Syndrome (RES) consortium pushed the button for the second round of trio exome sequencing, a pivotal event in the history of epilepsy genetics that led to the discovery of more than a dozen genes for developmental and epileptic encephalopathies. The fact that this critical juncture in the history of epilepsy gene discovery went largely unnoticed lies within the nature of research consortia – they form, they work, and they disperse. However, as EuroEPINOMICS was formative for me as a junior researcher, I wanted to dedicate this blog post to the research consortia of the early 2010s and the golden era of epilepsy gene discovery, when I was a EuroEPINOMICS kid.

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ICK, Juvenile Myoclonic Epilepsy, and the burden of proof

Pathogenic or benign. In 2018, ICK, coding for Intestinal-Cell Kinase, was reported as a novel causative gene in Juvenile Myoclonic Epilepsy (JME) in the New England Journal of Medicine. JME is one of the most common epilepsy syndromes, and the authors suggested that up to 7% of JME in their study may be explained by pathogenic variants in this gene, suggesting that, if applicable to all individuals with JME, it may provide a genetic diagnosis for an expected 500,000 individuals worldwide. In a reply to the initial study, the investigators of the EuroEPINOMICS-CoGIE, EpiPGX, Epi4K, and EPGP Consortia attempted to replicate these initial findings, but could not find any evidence in for a role of ICK in JME and indicated that the initial results may have arisen by chance and due to methodological issues. Given the potential implications for future research and therapy development in a relatively common epilepsy, the controversial ICK story is a good example to highlight why it is important to revisit the current consensus on when we consider a candidate a true disease gene and why a category mistake confusing variant pathogenicity for gene validity may result in false positive findings. Continue reading

Big data, ontologies, and the phenotypic bottle neck in epilepsy research

Unconnected data. Within the field of biomedicine, large datasets are increasingly emerging. These datasets include the genomic, imaging, and EEG datasets that we are somewhat familiar with, but also many large unstructured datasets, including data from biomonitors, wearables, and the electronic medical records (EMR). It appears that the abundance of these datasets makes the promise of precision medicine tangible – achieving an individualized treatment that is based on data, synthesizing available information across various domains for medical decision-making. In a recent review in the New England Journal of Medicine, Haendel and collaborators discuss the need in the biomedical field to focus on the development of terminologies and ontologies such as the Human Phenotype Ontology (HPO) that help put data into context. This review is a perfect segue to introduce the increasing focus on computational phenotypes within our group in order to overcome the phenotypic bottleneck in epilepsy genetics. Continue reading

The GABA link in Genetic Generalized Epilepsy

GGE. The Genetic Generalized Epilepsies (GGE) are common epilepsies in children and adults with a prominent genetic contribution. However, genetic risk factors for GGE have been more difficult than most researchers would have expected to pin down. Genome-wide association studies for common variants and association studies for ultra-rare variants have been able to identify several candidate genes, but much of the genetic risk for GGE remain unaccounted for. In a recent study in Lancet Neurology, we have tried a different approach to address the genetic contribution for GGE, looking at gene groups rather than single genes. Using this approach, we were able to detect a signal that would not have been found when looking at individual genes alone, a contribution of rare variants in genes for GABA-A receptors that reliably spans across three different cohorts. 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

The microdeletion landscape of Genetic Generalized Epilepsy

CNV. Structural genomic variations or Copy Number Variations (CNVs) significantly contribute to the genetic architecture of many neurodevelopmental disorders. However, given the enormous variation in the human genome in healthy individuals, the precise contribution of CNVs remains poorly understood. In a recent publication in PLOS Genetics, we were able to assess the microdeletion architecture in more than 1,000 patients with Genetic Generalized Epilepsy (GGE) compared to more than 5,000 controls. We found that microdeletions occur almost twice as often in GGE patients compared to controls, an analysis that revealed both known suspects and interesting candidates. 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

Publications of the week – Dravet Syndrome, TBC1D24, and CSTB

Issue 6/2015. Publications from the most recent issue of Epilepsia are very prominent in this week’s selection of publications. We discuss the frequency of Dravet Syndrome, a novel family with a TBC1D24 mutation, and the role of Cystatin B (CSTB) in Juvenile Myoclonic Epilepsy. Continue reading