VUS. The story begins with a patient in clinic. A young child with severe epilepsy, carrying a variant in SCN1A, the classic gene for Dravet Syndrome. But the variant is labeled a variant of uncertain significance (VUS). Dravet Syndrome is a clinical diagnosis, and the treatments we have today do not hinge on whether the variant is clearly pathogenic or not. But then we wonder whether a novel precision therapy could be an option, and we look up inclusion criteria and hesitate. Trial frameworks often require a variant to be pathogenic or likely pathogenic, and future precision medicine approaches in routine clinical care may require the same. For this patient, a VUS is a door that does not open. Here lies the quiet revolution in epilepsy genetics that is unfolding in the background: the refinement of variant interpretation itself.
Category Archives: SCN1B
The millennium variant – SCN1B, gene validity, and GEFS+
800 years. The discovery of SCN1B as a causative gene for Genetic Epilepsy with Febrile Seizures Plus (GEFS+) was one of the most pivotal moments in epilepsy genetics. This discovery not only shaped our understanding of the channelopathy concept, but also highlighted the importance of careful phenotyping. Therefore, it may be surprising that SCN1B took almost a quarter of a century to accrue sufficient evidence to be considered as a definite epilepsy gene. However, this is not the only aspect where SCN1B operates on its own time scale. In a recent publication, one of the most common disease variants in SCN1B could be traced back more than 800 years to a single founder event. Here is a 2023 update on the journey of one of the most well-known but also most mysterious epilepsy genes whose origins are lost in the depth of time. Continue reading