Transcriptomic analysis reveals distinct expression patterns in focal cortical dysplasia

Focal cortical dysplasia (FCD) is a common cause of drug-resistant epilepsy in children and adults and exhibits substantial clinical and histopathological heterogeneity. However, morphological classification alone does not fully explain variability in epileptogenicity, disease severity, or treatment response.

We aimed to define molecular mechanisms underlying FCD heterogeneity using integrated transcriptomic and regulatory analyses. RNA and small RNA sequencing (RNA-seq) were conducted on cortical tissue resected during epilepsy surgery from 66 patients with histopathologically confirmed FCD subtypes IA (n = 17), IIA (n = 25), and IIB (n = 24), along with 15 postmortem cortical control samples. Differential expression and weighted gene coexpression network analysis were used to identify coordinated transcriptional programs, and microRNA (miRNA) profiling was integrated to assess posttranscriptional regulatory mechanisms. Integrative multivariate analyses (DIABLO and sparse partial least squares discriminant analysis) were used to evaluate subtype discrimination, and findings were validated using an independent RNA-seq dataset.

FCD subtypes showed distinct but partially overlapping molecular profiles. FCD IA showed a comparatively subtle transcriptional profile, dominated by reduced expression of genes involved in cortical development, neuronal signaling, ion regulation, and metabolic stress. FCD IIA displayed a modest yet coherent molecular signature involving developmental and neuronal disruption, together with metabolic stress and autophagy. FCD IIB exhibited the most extensive transcriptional remodeling, including activation of antigen presentation pathways, complement activation, cytoskeleton reorganization, synaptic alterations, and extracellular matrix organization. Differential miRNA profiling identified shared miRNAs, including miR-320 family, miR-27a-5p, miR-142-5p, and miR-21-5p, alongside subtype-specific regulatory patterns. Integration of messenger RNA and miRNA data revealed concordant alterations, indicating that miRNA dysregulation may contribute to stabilization of subtype-specific transcriptional states.

These findings demonstrate that FCD is characterized by coordinated transcriptional and posttranscriptional network alterations that extend beyond morphological classification and may contribute to variability in epileptogenicity across subtypes.