# Somatic Mutation in Intractable Focal Epilepsy

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $733,446

## Abstract

PROJECT SUMMARY
Individuals with intractable focal epilepsy and normal structural imaging (non-lesional focal epilepsy, NLFE) pose
treatment challenges. When no lesion is detected, localization of the seizure focus is difficult and surgical
success elusive. It is unknown how focal seizures arise in cortex with radiographically normal structure, and
whether pathology below the resolution of standard 3T MRI is a common culprit. We recently demonstrated that
somatic mutations in SLC35A2, which encodes a UDP galactose transporter, account for some NLFE. Some
radiographically normal cases exhibited FCD1a, demonstrating that somatic SLC35A2 mutations can account
for seizure onset in structurally normal and abnormal cortex, and identifying SLC35A2 as the first gene underlying
FCD1a and NLFE. We recently found somatic brain variants in PLXNB1 and BRAF in cases with normal imaging
but FCD2a on pathology. PLXNB1 may represent the first non-mTOR gene in FCD2. We thereby demonstrated
brain somatic variants can result in radiographic NLFE, some with abnormal pathology. As gene identification
illuminates the biology of focal epilepsy and informs therapy, discoveries can have major clinical implications.
We will further explore the somatic genetics of radiographic NLFE, including 1) replication of gene discoveries
in new cases, additional gene identification, and deeper sequencing for lower-frequency pathogenic alleles; 2)
clarifying phenotypes associated with specific somatic mutations, 3) development of imaging to detect subtle
abnormalities; 4) correlation of variant allele frequency (VAF) with pathology and EEG from specific biopsy sites
within resected brain and 5) association of regional pathology with EEG when mutations are absent.
In Aim 1 We will define the somatic genetic landscape of NLFE. In surgical epilepsy samples, we will conduct
ultra-high-depth whole exome sequencing of brain resected from the seizure focus from individuals with NLFE
to identify additional somatic mutations in SLC35A2, PLXNB1, BRAF, and other genes. In Aim 2 we will define
genotype-phenotype correlations in NLFE. We will determine phenotypes associated with somatic mutations
in specific genes in a cohort of individuals with NLFE, focusing on age at onset of epilepsy, abnormalities on
presurgical advanced 3T and 7T MRI with computational post-processing, and histopathologic analysis of
resected tissue. In Aim 3 we will define the regional EEG, pathological, and allelic burden of pathogenic
somatic variants within NLFE. During epilepsy surgery, we will perform 4-6 biopsies from tissue destined for
resection using an MRI-localized, electrophysiology-guided procedure. We will characterize pathology and EEG
firing pattern in each biopsy, distinguishing the EEG-designated seizure focus (core) vs. surround (penumbra).
We will quantitatively genotype each biopsy for variants deemed pathogenic to establish per-biopsy VAF and
when mutations are absent, correlate EEG pattern with histopa...

## Key facts

- **NIH application ID:** 10063291
- **Project number:** 1R01NS114122-01A1
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Peter B Crino
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $733,446
- **Award type:** 1
- **Project period:** 2020-08-15 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10063291

## Citation

> US National Institutes of Health, RePORTER application 10063291, Somatic Mutation in Intractable Focal Epilepsy (1R01NS114122-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10063291. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*