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

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

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