Paired blood and brain tissue methylation biomarkers in focal cortical dysplasia.

Focal Cortical Dysplasia (FCD) is a common cause of drug-resistant epilepsy. These abnormalities arise during embryonic development and are challenging to classify due to their complex nature. The most recent classification update of FCD incorporates genetic and epigenetic results with other clinical data for the management of epilepsy associated with these lesions. Mutations in the mechanistic target of rapamycin pathway have been described in subtypes IIa and IIb of FCD. In this study, we aimed to study brain DNA methylation in human FCD samples and determine whether blood DNA methylation reflects epigenetic changes observed in brain tissue. We studied genome-wide methylation in 21 brain tissue samples (FCD; n = 13 and other pathologies; n = 8) resected from patients with medically intractable epilepsy along with matched blood samples from the same patients. These results were validated with 32 brain-blood matched samples. This study identified both unique and shared methylation signatures in brain and blood for FCD subty pes IIa and IIb and validated three methylation biomarkers (Interleukin-1 receptor accessory protein, Homeodomain-interacting protein kinase 2, and Chronomodulin) that differentiate these subtypes. Methyl-Binding Domain capture sequencing identified 676 551 methylated regions, covering 70% of cytosine-guanine dinucleotide sites in the genome. Adjustments for factors like age, gender, and disease duration were made before analysis. A total of 13 methylation biomarkers were identified for improved classification of FCD IIb from IIa. The three biomarkers showed high specificity and sensitivity, with an area under the curve score of 0.98 and P-value = 0.01. The study highlights the potential use of DNA methylation biomarkers as a non-invasive diagnostic tool for distinguishing between FCD subtypes, which could lead to more accurate treatment decisions for patients with epilepsy. The findings also underscore the importance of methylation patterns in understanding the pathophysiology of FCD.