SCN1A gain-of-function, paralogs, and the Philadelphia variant

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.

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A large-scale analysis of KCNQ2 variants – overcoming the functional bottleneck

KCNQ2. I have to admit we have not written about KCNQ2 for a while, which does not do justice to the role of KCNQ2 in human epilepsies. KCNQ2-related epilepsies represent some of the most common genetic epilepsies and almost exclusively present with neonatal seizures. Historically, KCNQ2 was identified in families with self-limiting neonatal seizures. Subsequently, disease-causing variants were also identified in neonatal developmental and epileptic encephalopathies (DEEs). While self-limiting epilepsies were attributed to protein-truncating variants, KCNQ2-related DEEs are attributed to dominant-negative variants. However, as in many other DEEs, this conceptual black-and-white distinction is somewhat oversimplified, and the genotype-phenotype correlation in KCNQ2-related disorders is more complex. In a recent study, we assessed a total of 81 KCNQ2 variants’ functional effects in parallel, leading to some unexpected results about the function of disease-related KCNQ2 variants. Here is what this first large-scale electrophysiological analysis of an epilepsy-related ion channel told us. Continue reading