Differential hierarchical cluster analysis of DNAm distinguished major FCD subtypes (ie, Ia, IIa, and IIb) from patients with temporal lobe epilepsy patients and nonepileptic controls. Targeted panel sequencing identified a novel likely pathogenic variant in DEPDC5 in a patient with FCD type IIa. However, no enrichment of differential DNAm or GE was observed in mechanistic target of rapamycin (mTOR) pathway-related genes. Here, DEPDC5 is linked to temporal lobe epilepsy.