ABSTRACT
Objectives:
Brain-limited pathogenic somatic variants are associated with focal pediatric
epilepsy, but reliance on resected
brain tissue samples has limited our
ability to correlate epileptiform activity with abnormal
molecular pathology. We aimed to identify the pathogenic variant and map variant
allele fractions (VAFs) across an abnormal region of epileptogenic
brain in a
patient who underwent stereoelectroencephalography (sEEG) and subsequent motor-sparing left frontal disconnection.
Methods:
We extracted genomic
DNA from peripheral
blood,
brain tissue resected from peri-sEEG
electrode regions, and microbulk
brain tissue adherent to sEEG
electrodes. Samples were mapped based on an anatomic relationship with the presumed seizure onset zone (SOZ). We performed deep panel sequencing of amplified and unamplified
DNA to identify pathogenic variants with subsequent orthogonal validation.
Results:
We detect a pathogenic somatic PIK3CA variant, c.1624G>A (p.E542K), in the
brain tissue samples, with VAF inversely correlated with distance from the SOZ. In addition, we identify this variant in amplified
electrode-derived samples, albeit with lower VAFs.
Discussion:
We demonstrate regional
mosaicism across epileptogenic
tissue, suggesting a correlation between variant burden and SOZ. We also validate a pathogenic variant from individual amplified sEEG
electrode-derived
brain specimens, although further
optimization of
techniques is required.