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

常见和罕见癫痫脑损伤患者的全面基因组生物标志物发现

• 批准号: 418080568
• 负责人: Professor Dr. Ingmar Blümcke
• 金额: --
• 依托单位: Cologne Center for Genomics
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/418080568?language=en
• 关键词: Comprehensive; genomic; biomarker; discovery; patients

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.

耐药局灶性癫痫是一个重大的健康负担和临床患者管理的主要挑战。尽管最近发现了基因，但三分之二的患者在基因检测后仍然呈阴性。皮质发育畸形（MCD）（包括局灶性皮质发育不良（FCD）和脑肿瘤）的体细胞变异研究一直处于小规模或仅针对基因子集。在更常见的癫痫性脑病变，如海马硬化症（HS）的遗传贡献仍然没有探索。这项研究将首次对1500个致癫痫性脑病变进行全面的遗传评估，我们的工作组有能力成功识别和翻译致病变异和遗传风险因素。目标1：我们将评估来自500例具有耐药性癫痫和组织病理学证实的病变的患者的手术切除的脑组织样本中的体细胞变异负荷：MCD=200，脑肿瘤=100，HS=200。我们将使用覆盖率> 300 x的全外显子组测序来鉴定疾病基因，并应用统计模型来鉴定具有同义与非同义变体比率偏差的基因。将引入前50个富集基因作为局灶性癫痫的新基因组，以在1，000例病例的独立样本队列中进行验证：MCD=400，脑肿瘤=200，HS=400）。目标2：我们将评估常见风险变异负担。与许多单基因疾病一样，尽管有相同的遗传缺陷，但局灶性癫痫患者的临床表现差异很大。然而，目前尚不清楚常见的多基因变异是否会影响整体疾病风险和/或临床表现。我们将对上述所有患者的基因型进行SNP阵列（目的1），以评估疾病贡献并测试先前表征的神经系统和神经精神障碍的多基因风险评分（n>40评分）。目的3：我们将在外显子组阴性FCD中进行全基因组的遗传变异探索。我们将检查深度（> 300倍）全基因组测序的实用性，并分析20名“外显子组阴性”FCD患者队列中的生殖系和体细胞非编码和大结构变异。目标4：我们将确定遗传同质的病理组，并检查其与临床生物标志物的关系，包括术后癫痫发作的自由。将对具有相同推定遗传病因或风险特征的较大患者组进行重新检查，以确定特定的临床表型，目的是改善诊断，患者护理和管理。由著名的主要研究人员组成的多学科小组，国际合作伙伴以及全球独特的具有深层表型的脑组织收集将确保该项目的成功执行。