Comprehensive genomic biomarker discovery in patients with common and rare epileptic brain lesions

点击翻译按钮获取中文摘要

Drug-resistant focal epilepsies represent a significant health burden and a major challenge for clinical patient management. Despite recent gene discoveries, two-third of patients remain negative following genetic testing. Somatic variant studies of Malformations of Cortical Development (MCD), including Focal Cortical Dysplasia (FCD) and brain tumors have been at small scale or targeted only a subset of genes. The genetic contribution in more common epileptic brain lesions such as Hippocampal Sclerosis (HS) remains unexplored. This study will be first to conduct a comprehensive genetic evaluation of 1500 epileptogenic brain lesions, and our working group is well positioned to successfully identify and translate disease-causing variants and genetic risk factors. Aim 1: We will assess somatic variant burden in surgically resected brain tissue samples from 500 patients with drug-resistant epilepsies and histopathologically confirmed lesions: MCD=200, brain tumors=100, HS=200. We will use whole exome sequencing with coverage of >300x to identify disease genes and apply statistical models to identify genes with deviations from synonymous to non-synonymous variant ratios. The top 50 enriched genes will be introduced as a new gene panel for focal epilepsies to be validated in an independent sample cohort of 1,000 cases: MCD=400, brain tumors=200, HS=400). Aim 2: We will assess common risk variant burden. As with many monogenetic diseases, despite the same genetic defects, patients with focal epilepsy have highly variable clinical presentations. Yet, it is unclear if common polygenic variation affects the overall disease risk and/or clinical manifestation. We will SNP-array the genotype of all patients included above (aim 1) to assess disease contribution and test polygenic risk scores for previously characterized neurological and neuropsychiatric disorders (n>40 scores). Aim 3: We will conduct genome-wide exploration of genetic variants in exome negative FCD. We will examine the utility of deep (>300x) whole genome sequencing and analyze germline and somatic non-coding and large structural variants in a cohort of 20 "exome negative" patients with FCD. Aim 4: We will identify genetically homogeneous pathology groups and examine their relationship with clinical biomarkers, including postsurgical seizure freedom. Larger groups of patients with the same presumptive genetic etiology or risk profile will be re-examined to identify specific clinical phenotypes, with the goal of improving diagnosis, patient care, and management. The multidisciplinary group of renown principle investigators, international collaboration partners as well the worldwide unique brain tissue collection with deep phenotypes will guarantee successful execution of the project.