# Matched tissue-blood whole-exome sequencing improves detection of genetic etiologies in pediatric drug-resistant epilepsy

## TL;DR

Using matched tissue-blood whole-exome sequencing improves the detection of genetic causes in children with drug-resistant epilepsy.

## Contribution

Matched tissue-blood WES increases diagnostic yield compared to blood-only testing in pediatric drug-resistant epilepsy.

## Key findings

- Matched tissue-blood WES identified genetic etiologies in 28.6% of patients, higher than blood-only WES or clinical evaluations.
- Somatic mosaic BRAF variants were detected in brain tissue but not in blood for two patients.
- DEPDC5 and TSC2 gene variants were found in both blood and brain tissue for four patients.

## Abstract

Improving the diagnostic rate of genetic etiologies in pediatric drug-resistant epilepsy (DRE) is of critical importance, as it provides valuable guidance for clinical management in this challenging patient population.

In this study, matched tissue–blood whole-exome sequencing (WES) was performed on lesional brain tissue and peripheral blood from 21 patients diagnosed with DRE who had undergone resective epilepsy surgery, in order to assess its diagnostic yield.

The final cohort therefore consisted of 21 pediatric patients with DRE. The patients’ ages ranged from 0.2 to 10.7 years, with a mean age of 5.2 years. Eleven were male and ten were female. Matched tissue-blood WES successfully identified the genetic etiology in six pediatric patients with drug-resistant epilepsy, yielding a diagnostic rate of 28.6% (6/21). This rate was higher than that achieved using blood-only WES (19.0%, 4/21) or clinical and imaging evaluations alone (9.5%, 2/21). Among these six positive cases: Patients 2 and 7 carried deletion and splice-site variants in the DEPDC5 gene, respectively, and these findings were detected in both blood and diseased brain tissue; Patients 14 and 20 both had missense variants in the TSC2 gene, detected in both blood and diseased brain tissue; Patients 8 and 16 had negative blood WES results, but somatic mosaic BRAF variants were detected in the diseased brain tissue, with mosaic levels of 20.2% and 13.5%, respectively.

Matched tissue–blood WES facilitates the diagnostic yield in pediatric drug-resistant epilepsy, highlighting its critical value in detecting genetic variants that may be missed by blood-only testing and providing essential support for precision diagnosis and therapy.