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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DNM1 and when transcripts matter more than genes

What comes next. Earlier this month, Ingo made a bit of a splash at the American Epilepsy Society Annual Course, with his surprising comment that, in some contexts, “genes don’t matter.” This was in reference to transcripts and gene expression, which ultimately determine if and how variants can cause disease. In this post, I wanted to explore this idea, diving into the world of transcripts and their increasing relevance in approaching diagnosis and treatment of genetic epilepsies and neurodevelopmental disorders. And I wanted to share one of the most surprising findings in epilepsy genetics in 2022, namely, how examining transcripts rather than genes helped us understand how an intronic variant can be dominant-negative. Continue reading