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 Epilepsy Genetics Initiative – novel diagnoses through exome re-analysis

The negative exome. Despite writing a lot about the power of next generation sequencing technologies to provide a genetic diagnosis in individuals with severe epilepsies, it is important to remember that most exome tests performed in a diagnostic setting are negative. Even the most optimistic studies do not find a diagnostic yield that exceeds 40%. However, what can be done about the 60-70% of patients who had undergone exome sequencing, the current gold-standard diagnostic testing, but have received a negative test result? A systematic re-analysis after 12-24 months is currently considered one possibility to make sense of existing exome data. In a current publication, the Epilepsy Genetics Initiative (EGI) reports their results of a systematic research-based re-analysis in 166 individuals with epilepsy. In eight individuals, a novel diagnosis could be achieved, including novel genes not known at the time of the initial report and novel mechanisms such as alternative exons. With a diagnostic rate of 6%, this study provides a unique benchmark of what can be expected when exomes initially come back as negative. Continue reading