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

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

Publications of the week: SLC13A5, SNAP25, and JME fMRI endophenotypes

Catching up. It has been a while since we posted a section on the recent publications in the field of epilepsy genetics. We are trying to catch up by briefly discussing three publications that appeared in the last two weeks. Here is what you should know about citrate transporters in epileptic encephalopathy, an STXBP1-interacting protein, and fMRI endophenotypes in Juvenile Myoclonic Epilepsy (JME). Continue reading

Publications of the week – SCN8A, CNTNAP4, EML1, and SCN1A

Catching up. This week’s review of recent publications might be relevant for you because it adds new pertinent details to known epilepsy genes and discusses novel gene findings that might be applicable in clinical practice. This post covers publications on SCN8A in epileptic encephalopathy, CNTNAP4 and interneurons, EML1 in brain malformations, and the meaning of SCN1A variants in small epilepsy families. Continue reading

A PhD in genomics – lessons learned

This is it! With finishing my PhD I have become an “adult” member of the scientific Graduierungcommunity. I grew out of a bachelor in biochemistry on transfection methods in neuronal cell lines, a research semester in Canberra with focus on B-cell immunology and master into a  PhD in epilepsy genomics. I was involved in the EPICURE IGE copy number projects and recently my work changed to the analysis of rare variants in RE and IGE in the EUROepinomics framework. During this time I was involved in the identification of variants in RBFOX genes and GRIN2A as well as other risk factors which are currently in review. I share my experience and thoughts and hope they help others who are about to or have just started their thesis. The aspects reflect my personal view and some are specific for graduation in disease genomics. Continue reading

Identifying core phenotypes – epilepsy, ID and recurrent microdeletions

Triad. There are three microdeletions in particular that increase the risk for the Idiopathic/Genetic Generalized Epilepsies (IGE/GGE). This triad includes microdeletions at 15q13.3, 16p13.11 and 15q11.2, which are hotspot deletions arising from the particular architecture of the human genome. While the association of these microdeletions with epilepsy and other neurodevelopmental disorders including autism, intellectual disability and schizophrenia is well established, the core phenotype of these variants remains elusive, including the question whether such a core phenotype actually exists. In a recent paper in Neurology, Mullen and collaborators zoom in on a possible core phenotype of these microdeletions. The authors investigate a phenotype in which these microdeletions are particularly enriched: generalized epilepsy with intellectual disability. Continue reading

Dysregulation of a microRNA in the 22q11.2 microdeletion

Genotype to phenotype. Recurrent microdeletions at various sites in the human genome are known risk factors for a broad range of neurodevelopmental disorders including epilepsy, autism, intellectual disability and schizophrenia. Despite the fact that the pathogenic role is well established, the mechanisms linking the microdeletion to the neurodevelopmental phenotype remain obscure. In contrast to monogenic disorders, various genes are included and functional studies are difficult. Now, a recent paper in Cell examines the role of a specific microRNA that is dysregulated in the 22q11.2 microdeletion. The results are surprising. 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

Traveling with Lennox – the petit mal triad

Lights on and lights out. Staring spells, petits mals, pyknolepsy and absence seizures. The brief spells that occur in patients with epilepsy have riddled neurologists for centuries. This became clear to me when Zaid Afawi and myself saw an epilepsy family in the West Bank on Sunday. When are staring spells epileptic and what kind of seizures are they? For me, this was a good opportunity to read Lennox’s thoughts on this. Eventually, after a long day under the Middle Eastern sun, I fell asleep over the chapter on absence status. Continue reading

Standing on the shoulders of giants: the EPICURE GWAS on Idiopathic Generalized Epilepsy

Pushing the reset button. The history of epilepsy genetics can broadly be distinguished into two major eras: the time before September 4th, 2012 and everything after this. September 4th, 2012 was the date that the first large genome-wide association study in IGE/GGE was published online in Human Molecular Genetics. Each of the >100 association studies in IGE listed in PubMed is now dated and needs to measure up against the current study, which will likely be remembered as the “EPICURE study”. The results of the EPICURE study are surprising and upset our conventional wisdom of what causes one of the most common forms of epilepsy. Continue reading