Between the ion channels. Rather than going “beyond the ion channel,” in this post, we aim to look between them. We want to dive into a study where examining the group of epilepsy-related sodium channels was initially more informative than the single gene itself—even when that gene was SCN1A, the most established epilepsy gene. A recurrent SCN1A variant turned out to be part of an emerging, previously underappreciated gain-of-function spectrum. Here, we discuss the unusual phenotype of SCN1A gain-of-function variants and how we are currently working on integrating information on paralogs into the official ACMG variant curation criteria.
Genetic architecture. Our reference dataset for genetic variation in humans has become so large that we can increasingly ask the question whether the distribution of genetic variants tells us something about genes and regions within genes without knowing anything about what these genes actually do. For example, it is well established that genes with fewer protein-truncating variants than expected are much more likely to be causative genes for epilepsy and neurodevelopmental disorders than genes that have an average number of these variants. A recent publication in Nature Genetics takes this approach one step further by looking at specific regions within genes rather than entire genes, a somewhat interesting approach that the authors introduce by discussing bullet damage to airplanes in World War II. Continue reading
Online. Last week, we held the first online symposium on “Rare Genetic Variants Associated with Neurodevelopmental Disorders”. The meeting covered seven topics which included different genomic approaches used to unravel the genetic architecture of neurodevelopmental disorders and cognitive traits. In total, 117 participants joined the meeting with a peak of 72 participants listening to a presenter. Continue reading
VUS. In recent EpiGC posts, we discussed how laboratories evaluate sequence variants and the challenges of communicating variants of uncertain significance (VUS) to patients. While VUS results can be frustrating, by working together clinicians and laboratories may accumulate additional evidence that enables a more definitive variant classification. But how, you ask? Well, there are several ways . . .
Evidence and absence. There is a time before and after ExAC, the gigantic variant repository based on more than 60,000 exomes sequenced at the Broad Institute. ExAC was released in October 2014 and has suddenly provided the community with access to variant data of roughly ten times more individuals than previous resources. But what happens when you check variants that were previously considered pathogenic and they are seen at low frequency in ExAC? Welcome to the Zero ExAC problem, providing us with a taste of the complications that epilepsy gene variant interpretation will face in the future. Continue reading