Pathophysioloy of non-classic epileptic encephalopathies (EE)

癫痫性脑病（EE）个别罕见，但集体常见的中枢神经系统疾病（CNS）。情感表达是一种严重的顽固性癫痫，通常始于儿童时期，并伴有较差的认知结果。虽然癫痫性脑病可由于中枢神经系统的可识别病变（如畸形）而发生，但在大多数病例中无法确定病因。遗传因素是有牵连的，但直到最近，发现潜在的遗传改变被证明是难以捉摸的。随着高通量测序技术的出现，可以确定包括婴儿痉挛（IS）和Lennox-Gastaut综合征（LGS）在内的经典癫痫性脑病的遗传基础。新生突变被发现对这些疾病的病因有重要贡献，目前正在进行大规模的合作研究，以增加IS和LGS病例的比例。在这些国际研究中，申请人已经作为项目负责人和协调人发挥了主导作用。在目前的建议中，我们的目标是将我们的基因鉴定策略扩展到更广泛的情感表达，例如不能归类为传统综合征的非经典形式。这些情感表达在临床实践中构成了主要的诊断和治疗挑战，迄今尚未纳入系统研究。有强有力的证据表明，新生突变在这些疾病中起着重要作用，这在临床上是高度相关的，目前没有足够的治疗选择。我们的目标是使用三重奏外显子组测序在100名患者-父母三重奏中识别新生突变，并使用50个最有希望的候选基因的基因面板分析对500名患者进行随访分析。我们将对5种最有希望的蛋白进行功能分析。鉴于缺乏国家和欧洲规模的可比项目，本研究将为开展迄今为止被忽视的广泛的情感表达的未来确认和功能研究提供必要的基础。当前的提案申请是申请人在2012年12月提交的先前提案的重新提交。我们相信我们已经充分处理了审稿人和DFG小组的意见和建议。此外，我们在以下背景下提出建议：(1)该领域的最新发展改变了本申请的某些方面；(2)申请人专业知识的进步，特别是在下一代测序技术方面。我们还强调了该申请在该领域整体竞争和资金格局中的重要性，因为该提案将允许申请人确立其在该领域的领导者角色。

Epileptic encephalopathies (EE) are individually rare but collectively common disorders of the central nervous system (CNS). EE are severe, intractable epilepsies that usually start in childhood and are associated with a poor cognitive outcome. While epileptic encephalopathies can occur as the result of identifiable lesions in the CNS such as malformations, a causative factor cannot be identified in a broad subset of cases. Genetic factors are implicated, but until recently, the discovery of the underlying genetic alterations turned out to be elusive. With the advent of high-throughput sequencing technologies, a genetic basis could be identified for the classic epileptic encephalopathies including Infantile Spasms (IS) and the Lennox-Gastaut syndrome (LGS). De novo mutations were found to contribute significantly to the etiology of these conditions and large, collaborative studies are currently performed to increase the fractions of cases explained in IS and LGS. In these international studies, the applicants are already taking a leading role as project leaders and coordinators. In the current proposal, we aim to expand our gene-identification strategy to a broader range of EE such as the non-classical forms which cannot be classified into the traditional syndromes. These EE, which pose a major diagnostic and therapeutic challenge in clinical practice, have not been included in systematic studies so far. There is strong evidence that de novo mutations play a large role in these conditions, which are clinically highly relevant and currently without sufficient treatment options. We aim to identify de novo mutations using trio exome sequencing in 100 patient-parent trios with follow-up analysis in 500 patients using a gene panel analysis of the 50 most promising candidate genes. We will perform functional analysis in the 5 most promising proteins. Given the absence of comparable projects on a national and European scale, this study will provide the necessary foundation to launch future confirmation and functional studies on a broad range of so far neglected EE. This current proposal application is a resubmission of a previous proposal by the applicants in December 2012. We believe that we fully address the comments and suggestions of the reviewers and of the DFG panel. In addition, we put out proposal in context to (1) recent developments in the field that change some aspects of this application and (2) progress in the expertise of the applicants particularly with respect to next-generation sequencing technologies. We also address the importance of the application in the context of overall competition and funding landscape in this area, as this proposal will allow the applicants to establish their role as leaders in the field.