Genetic and Molecular Profile Analysis Through Whole-Exome Sequencing of Patients with Type III Focal Cortical Dysplasia Undergoing Surgical Treatment

• Grant number: 25/11439-0
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: November 01, 2025
• End date: October 31, 2026
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Marcelo Volpon Santos
• Grantee: Rafael Andrade Cruz
• Host Institution: Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da USP (HCMRP). Secretaria da Saúde (São Paulo - Estado). Ribeirão Preto , SP, Brazil

Abstract

Introduction: Type III Focal Cortical Dysplasia (FCDIII) represents a significant diagnostic and therapeutic challenge in the context of refractory epilepsy, especially in pediatric populations. This malformative condition of cortical development is characterized by dysplastic changes associated with other acquired or congenital brain lesions, such as hippocampal sclerosis, tumors, or traumatic sequelae. Although surgery is often the primary intervention for seizure control, the genetic mechanisms underlying FCDIII remain poorly understood, limiting advances in prognostic stratification and targeted therapies. Materials and Methods: This study proposes a genetic and molecular analysis of patients with FCDIII through Whole-Exome Sequencing (WES), using brain tissue and peripheral blood samples collected during clinically indicated surgical procedures. Approximately 15 patients previously submitted to epilepsy surgery at a specialized center will be included. Samples will undergo rigorous DNA extraction, followed by sequencing and bioinformatic analysis. Tools such as GATK, MuTect, Strelka, and Variant Effect Predictor will be used for variant detection and annotation. Filtering will follow strict quality and rarity criteria, supported by databases including gnomAD, ClinVar, OMIM, and COSMIC. Results: The study aims to identify somatic and germline variants associated with the pathogenesis of FCDIII, correlating these genetic alterations with clinical data such as age at seizure onset, seizure type, lesion lateralization, postoperative evolution, and surgical outcomes. Statistical analysis will include association tests between variants and clinical outcomes, as well as a description of the frequency of somatic and germline mutations and the identification of recurrent molecular pathways or genes with potential diagnostic or prognostic value. Conclusion: It is expected that the results will contribute to advancing the understanding of the genetic mechanisms involved in Type III Focal Cortical Dysplasia, providing a foundation for future diagnostic, prognostic, and therapeutic strategies that are more precise and individualized. The integration of molecular and clinical data may enhance the role of genomics in the management of refractory epilepsy associated with malformations of cortical development. (AU)