Interpreting Variants of Uncertain Significance in Dravet Syndrome

In “Interpreting Variants of Uncertain Significance in Dravet Syndrome,” our panel explores one of the most challenging aspects of genetic testing: the interpretation and clinical management of variants of uncertain significance (VUS). Expert faculty discuss how clinicians should approach inconclusive genetic findings, emphasizing that a VUS is neither a positive nor a negative result and should not automatically be assumed to explain a patient’s epilepsy. The panel reviews the major categories of genetic testing results—negative findings, pathogenic or likely pathogenic variants, and VUS—and highlights common pitfalls that can occur when interpreting these reports in clinical practice.

The discussion focuses on practical strategies for evaluating uncertain findings, including periodic reanalysis of genetic data, use of specialized databases and prediction tools, family testing, and consultation with genetics experts when clinical suspicion remains high. Panelists explain how advances in genetic knowledge continue to refine variant interpretation and why current recommendations support reassessment of genetic findings over time. They also review the importance of correlating genetic results with clinical presentation, particularly in patients with suspected Dravet syndrome and SCN1A-related epilepsies.

Throughout the conversation, the panel emphasizes the value of multidisciplinary collaboration among neurologists, geneticists, genetic counselors, and diagnostic laboratories when evaluating uncertain findings. Faculty discuss how a strong clinical phenotype can help prioritize variants for further investigation and identify situations in which additional testing or research-based evaluation may be warranted. The episode highlights the evolving nature of genetic interpretation and provides clinicians with practical guidance for navigating uncertainty while maintaining a patient-centered approach to care.

In the next episode, “Current Treatment Strategies for Dravet Syndrome,” panelists will review the current standard of care for Dravet syndrome, including first-line and adjunctive treatment options, treatment goals, and factors that influence therapy selection. The panel will also explore the potential role of disease-modifying therapies in addressing long-term neurological outcomes beyond seizure control.