Detection of somatic and germline pathogenic variants in adult cohort of drug-resistant focal epilepsies

• Published in: Epilepsy & behavior 2024-04, Vol.153, p.109716-109716, Article 109716
• Main Authors: Ferri, L., Menghi, V., Licchetta, L., Dimartino, P., Minardi, R., Davì, C., Di Vito, L., Cifaldi, E., Zenesini, C., Gozzo, F., Pelliccia, V., Mariani, V., de Spelorzi, Y.C.C., Gustincich, S., Seri, M., Tassi, L., Pippucci, T., Bisulli, F.
• Format: Article
• Language: English
• Subjects: Adult; Drug Resistant Epilepsy - genetics; Drug Resistant Epilepsy - surgery; Epilepsies, Partial - diagnosis; Epilepsies, Partial - genetics; Epilepsy; Epilepsy surgery; Focal Cortical Dysplasia; Germ Cells - pathology; Histopathological diagnosis; Humans; Malformations of Cortical Development - pathology; Malformations of Cortical Development, Group I; mTOR pathway; Seizures; Somatic mutations; Surgical Outcome; TOR Serine-Threonine Kinases
• ISSN: 1525-5050; 1525-5069
• DOI: 10.1016/j.yebeh.2024.109716

•Investigating the prevalence of mTOR mutations in brain specimens of 78 patients.•Pathogenic mTOR variant found in 22% of cases, only in FCDII/TSC subgroup.•Patients carried pathogenic variant showed good surgical outcomes.•Phenotype-genotype correlation showed distinctive features in mutated FCDII/TSC.•Advocated mTOR systematic screening in brain specimens as a potential biomarker. This study investigates the prevalence of pathogenic variants in the mechanistic target of rapamycin (mTOR) pathway in surgical specimens of malformations of cortical development (MCDs) and cases with negative histology. The study also aims to evaluate the predictive value of genotype-histotype findings on the surgical outcome. The study included patients with drug-resistant focal epilepsy who underwent epilepsy surgery. Cases were selected based on histopathological diagnosis, focusing on MCDs and negative findings. We included brain tissues both as formalin-fixed, paraffin-embedded (FFPE) or fresh frozen (FF) samples. Single-molecule molecular inversion probes (smMIPs) analysis was conducted, targeting the MTOR gene in FFPE samples and 10 genes within the mTOR pathway in FF samples. Correlations between genotype-histotype and surgical outcome were examined. We included 78 patients for whom we obtained 28 FFPE samples and 50 FF tissues. Seventeen pathogenic variants (22 %) were identified and validated, with 13 being somatic within the MTOR gene and 4 germlines (2 DEPDC5, 1 TSC1, 1 TSC2). Pathogenic variants in mTOR pathway genes were exclusively found in FCDII and TSC cases, with a significant association between FCD type IIb and MTOR genotype (P = 0.003). Patients carrying mutations had a slightly better surgical outcome than the overall cohort, however it results not significant. The FCDII diagnosed cases more frequently had normal neuropsychological test, a higher incidence of auras, fewer multiple seizure types, lower occurrence of seizures with awareness impairment, less ictal automatisms, fewer Stereo-EEG investigations, and a longer period long-life of seizure freedom before surgery. This study confirms that somatic MTOR variants represent the primary genetic alteration detected in brain specimens from FCDII/TSC cases, while germline DEPDC5, TSC1/TSC2 variants are relatively rare. Systematic screening for these mutations in surgically treated patients' brain specimens can aid histopathological diagnoses and serve as a biomarker for positive surgical outcomes. Certain