Expanding epilepsy genetics beyond the exome

The overwhelming majority of children with epileptic encephalopathy do not respond to current therapeutics, this contributes to cognitive decline and poor outcome for most patients. The first step towards development of novel therapeutics for these disorders is to identify the underlying causes that will foster new lines of research. Over the past few years, tremendous progress has been made in identifying novel genetic causes of epilepsy. We know now that there are de novo mutations in over 50 genes that can cause this disorder and mutations in these genes account for around a quarter of all cases. While there are many more genes still to be identified, they are unlikely to account for all cases, and we need to consider novel genetic paradigms. This research will focus on the role of de novo mutations in alternative exons in the sodium channels, SCN1/2/8A. Previously we have identified five variants in an SCN1A alternative exon that may lead to aberrant splicing, premature truncation and haploinsufficiency. The aim of this study is to characterize these variants in stem cell models, but also to screen similar candidate alternative exons in SCN1/2/8A in patients with epileptic encephalopathy. These aims are parallel to the overall mission of our lab to define the genetic basis of epilepsy, understand disease mechanisms and develop new therapeutics.