Authors :
Presenting Author: Fawzi Babtain, MBBS – King Faisal Specialist Hospital and Research Center -Jeddah
Sarah Al Shehri, MBBS – King Faisal specialist hospital and research centre- Jeddah
Adelah Al Turaifi, MBBS – King Faisal specialist hospital and research centre - Jeddah
Mohammed Al Mansour, MBBS – King Faisal specialist hospital and research centre - Jeddah
Afnan Al Khotani, MBBS – King Faisal specialist hospital and research centre - Jeddah
Saleh Baeesa, MD, FRCSC – King Faisal specialist hospital and research centre - Jeddah
Rawan Daghistani, MBBS – King Faisal Specialist Hospital and Research Center
Faisal Al Suliman, MSc – King Faisal specialist hospital and research centre - Jeddah
Youssof Al Hawsawi, MD – King Faisal specialist hospital and research centre - Jeddah
Mohammed Imran Khan, MD – King Faisal specialist hospital and research centre - Jeddah
Youssof Al Said, MBBS – King Faisal specialist hospital and research centre - Jeddah
Rationale:
Focal cortical dysplasia (FCD) significantly contributes to drug-resistant epilepsy (DRE), with its genetic underpinnings requiring further elucidation. This study employs whole-exome sequencing (WES) and gene network analysis to comprehensively investigate pathogenic mutations, gene clustering patterns, and their functional associations in DRE and FCD.
Methods:
We retrospectively reviewed patients with DRE and confirmed or suspected FCD, who were seen between 2022 and 2024, diagnosed by surgical pathology or neuroimaging. Whole exome sequencing (WES) data were analyzed to identify gene mutations. Subsequently, gene network analysis was performed to explore clustering patterns, functional associations, and the identification of pathogenic modules and independent high-impact variants.
Results:
We studied 83 patients with DRE (mean age: 31 years, mean age at onset: 11 years). MRI abnormalities were detected in 67% of cases, with FCD as the predominant lesion (56%), followed by nodular heterotopia (12%). A total of 62 gene mutations were identified, of which 24 were known to be associated with epilepsy (Figure 1). Genetic network analysis demonstrated DRE's heterogeneous molecular profile and contributed to the interpretations of variants. SCN1A formed a central pathogenic module with VUS genes (e.g., GRIN2A, KCNC1), implying its pathogenic effects extend through shared ion channels and/or neurotransmitter pathways, thus prioritizing these VUS for functional follow-up. Separately, DEPDC5 (pathogenic) and NPRL3 (pathogenic) indicated a distinct mTOR-related axis, suggesting independent yet critical mechanisms. Furthermore, 10 mutations were identified as rare or potentially novel (Figure 2). Among these, PGAP1 (likely pathogenic) formed the core module interacting with novel VUS genes, suggesting potential module-based pathogenicity. In contrast, novel CHRNA4 (pathogenic), DEPDC5 (pathogenic), and VARS1 (likely pathogenic) variants were identified in isolation within their respective network views, suggesting distinct primary pathogenic pathways (table 1).
Conclusions:
Our integrated network analysis reveals the profound genetic heterogeneity of DRE and FCD, identifying diverse known and potentially novel pathogenic mutations while crucially delineating distinct pathogenic gene modules (e.g., SCN1A, DEPDC5/NPRL3) and independent high-impact genes. Novel mutations, some of which form unique modules, underscore their significant contribution. These findings guide targeted functional studies, particularly VUS prioritization, and necessitate further investigation into shared mechanisms and longitudinal genotype-phenotype correlations.
Funding: None