Somatic variants in epilepsy - advancing gene discovery and disease mechanisms

In the past ten years, there has been increasing recognition that cells can acquire genetic variants during cortical development that can give rise to brain malformations as well as nonlesional focal epilepsy. These often brain tissue-specific, de novo variants can result in highly variable phenotypes based on the burden of a variant in specific tissues and cells. By discovering these variants, shared pathophysiological mechanisms are being revealed between clinically distinct disorders. Beyond informing disease mechanisms, mosaic variants also offer a powerful research tool to trace cellular lineages, to study the roles of specialized cell types in disease presentation, and to establish the cell-type specific genomic consequences of a variant.