EUROCORES: Genetics of the Rare Epilepsy Syndromes (EuroEPINOMICS)

Genetics of Rare Epilepsy syndromes The epilepsies represent common disorders with a strong genetic impact. Up to 10% of the patients with epilepsy suffer from rare epilepsy syndromes (RES). This means that if each syndrome is rare, together they represent a considerable number of patients. Lately, the strong genetic impact on seizure disorders has been well documented, and the impact is particularly prominent in RES. A monogenic etiology has been detected in both familial forms, such as in the syndrome GEFS+ and in sporadic forms, such as Dravet syndrome. The vast majority of genes for RES are still largely unknown. New high throughput screening methods, such as whole exome sequencing and large scale copy number variation analysis, have paved the way for new approaches to genetically map RES. The aim of this study has been to genetically map different forms of RES through a collaborative project, namely through the European consortium EuroEpinomics. The Norwegian part of this collaborative study has been a PhD project led by Kaja Selmer at the Dept. of Medical Genetics, Oslo University Hospital. PhD student and MD Roar Fjær has since 2012 performed his PhD work, studying the genetics of rare, monogenic epilepsies. Fjær and collaborators have studied several families with different monogenic epilepsies. In a family with basal ganglia calcifications and genetic generalized epilepsy, exome sequencing of the patients revealed mutations in both the SLC20A2 gene (known to cause familial brain calcifications) and in the CHRNB2 gene (known to cause epilepsy). The findings support seizures as part of the phenotypic spectrum of SLC20A2-related familial brain calcifications; however, the present phenotype may also result from additional genetic influence, such as the identified missense variant in the CHRNB2 gene. In collaboration with Farrukh Chaudhry and his group, Fjær provide novel insight to the pathomechanisms of progressive myoclonus epilepsy (PME) through their identification of a novel homozygous mutation in the KCTD7 gene in two brothers with a severe form of PME. This gene has previously been implicated in PME, however the underlying pathomechanisms have been elusive. In their work, Fjær and collaborators demonstrate the impact of the dysfunctional protein on K+ fluxes, neuronal membrane potential and neurotransmitter synthesis, shedding light on a hitherto unknown pathogenesis of PME. Lastly, in collaboration with the Norwegian Expert Centre for Rare Epilepsy-related Disorders, the Department of Pathology and the Department of Dermatology at Oslo University Hospital, Fjær has studied the genetic and molecular causes of Sturge-Weber syndrome (SWS). SWS is a rare neurocutaneous disorder that involves dilated post-capillary venules in the dermis of the skin and in the leptomeninges. It has been postulated to be caused by a somatic mutation, due to its well-circumscribed borders, usual unilaterality and absence of systemic symptoms other than from affected tissues. This hypothesis was confirmed in 2013 when an activating missense mutation was found in the GNAQ gene. The activating somatic mutation has been reported to cause 80-90% of the SWS cases tested until now. In this Norwegian study Fjær et al. aimed to investigate the genetic cause of SWS in a cohort of Norwegian patients and to explore the underlying mechanisms of disease development. They investigated different cell populations from biopsies from affected and unaffected skin from six patients recruited from the Norwegian registry of Sturge-Weber patients. The main hypothesis was that SWS primarily is an endothelial disease, and applied next generation sequencing techniques to study DNA in endothelial cells, fibroblast, keratinocytes and whole dermis. Patients negative for the known GNAQ variant underwent whole exome sequencing at depth ~ 400X to search for new causal mutations. Five out of six patients had the known mutation in GNAQ. In the remaining patient, a mutation in a novel gene which is yet not acknowledged as involved in the pathogenesis of SWS was identified. The mutation was found in all successful endothelial cultures, and was enriched in endothelial laser-microdissected tissue. Mutations causing Sturge-Weber syndrome therefore probably arise in angioblasts. In conclusion, Fjær et al. identify a novel cause of SWS and reveal important information regarding its pathogenesis. This PhD project thus reveals novel information on the genetic causes of rare epilepsy syndromes, and in addition contributes to improved understanding of the underlying pathogeneses. Increased knowledge on the underlying mechanisms of epilepsy development is crucial to reach our overall goal of improving follow-up and treatment of epilepsy patients.

Genetic mapping of monogenic epilepsies - a part of the collaborative research project (CRP) "Genetics of the rare epilepsy syndromes". Background: The epilepsies represent common disorders with a strong genetic impact. While many epilepsies can be class ified into well defined syndromes, up to 10% of the patients with epilepsy suffer from rare epilepsy syndromes (RES). Although each syndrome is rare, together they represent a considerable number of patients and the impact of RES on society and health car e budget is enormous. The strong genetic impact in seizure disorders is well documented and is particularly prominent in RES. A monogenic etiology has been detected in both familial forms, such as in the syndrome Generalized Epilepsy with Febrile Seizur es Plus, and in sporadic forms, such as Dravet syndrome. The identification of the disease causing mutations and genes has led to a better understanding of the pathophysiology of epilepsy and molecular findings in RES have shown to be risk factors also fo r more common forms of epilepsy. The vast majority of genes for RES are still unknown. New high throughput screening methods, such as whole exome sequencing and large scale copy number variation analysis, have paved the way for new approaches to genetical ly map RES. Aim: To genetically map different forms of RES through a European collaborative project. Material: Patients and cohorts from different collaborators in this CRP will be pooled. Norwegian patients with RES will be recruited from the Departme nt of Complex Epilepsy and the Department of Medical Genetics (Oslo University Hospital). Methods: Methods available in Norway are genome wide linkage analysis with single nucleotide polymorphism markers, large scale CNV analysis and whole exome sequenci ng. Importance: This international CRP will make a platform for a European approach to decipher the genetic basis of RES. Hopefully; an improved understanding of the underlying causes of RES will translate in to novel diagnostic and therapeutic avenues for patients suffering from epilepsy.