# Clinical genetics of drug-resistant epilepsy with focal cortical dysplasia

> **NIH NIH R01** · CLEVELAND CLINIC LERNER COM-CWRU · 2021 · $655,255

## Abstract

Project Summary (30 lines max; currently at 27 lines)
About one-third of people with epilepsy do not respond to currently available drug regimens, though many have
drug-resistant focal epilepsy amenable to surgical treatment. Among the most common epilepsy-associated
structural brain lesions are Focal Cortical Dysplasias (FCDs). FCDs are malformations of cortical development
where the affected neurons fail to migrate in the proper neocortex formation in utero. Somatic variants in about
10-20 genes have been reported as the underlying cause for a subset of FCDs1–13. However, we and others
have shown that 60-90% of patients with FCD type I (FCD I) and FCD type II (FCD II) lack any genetic
abnormality when using currently available testing methods. More strikingly, only a single gene has been
identified in FCD I12 to date. One reason could be that all previous genetic studies in FCD were observational
studies in candidate genes without rare variant burden testing against controls and have been performed in
small (n<77), poorly characterized, cohorts. None of these studies investigated copy number variants or
chromosomal alterations at the somatic level. Also, RNA dysregulation in FCD samples has not been explored
yet. Here, we propose the most comprehensive genetic analysis to date of a unique cohort of FCD I and II
patients with unprecedented deep clinical phenotyping. Our cohort is >13 times larger than any previously
published FCD I and II cohort. Combined with controls, this cohort enables the first rare variant burden analysis
for FCDs to confirm proposed and discover novel FCD-associated genes. In addition, we are the first to
generate single-nucleus RNA sequencing data from the brain tissue of FCD patients to study transcriptome-
level alterations associated with FCD I and II and genetic subtypes. Project hypothesis: Our comprehensive
and novel approach using well-characterized brain tissues and paired blood samples from patients with
epilepsy due to FCD I or FCD II will identify novel FCD causal genes and variants with clear diagnostic and
therapeutic implications. Impact: A better understanding of the genetic basis of FCD etiology will lead to the
introduction of novel gene-based diagnostic strategies and targeted drugs to fully manage a patient's seizures
while avoiding the spectrum of side effects typically associated with current therapeutic interventions. AIM 1:
Identify novel causal genes for FCD I and FCD II with germline and somatic brain variant burden. Aim 2:
Identify disease-associated somatic copy number variants (CNVs) and loss-of-heterozygosity (CN-LOH)
structural variants associated with FCD I and FCD II. Aim 3: Analyze resected brain tissues by single-nucleus
RNA-seq (snRNA-seq) to identify cell type-specific transcriptional alterations associated with FCD
histopathologies and with specific mutations.

## Key facts

- **NIH application ID:** 10209030
- **Project number:** 1R01NS117544-01A1
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** DENNIS LAL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $655,255
- **Award type:** 1
- **Project period:** 2021-04-15 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10209030

## Citation

> US National Institutes of Health, RePORTER application 10209030, Clinical genetics of drug-resistant epilepsy with focal cortical dysplasia (1R01NS117544-01A1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10209030. Licensed CC0.

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