Genetic mechanisms of epileptic encephalopathies

癫痫性脑病（EEs）是儿童期发病的治疗抵抗性癫痫，伴有发育迟缓和各种其他合并症，如共济失调或肌张力障碍。总的来说，EEs占所有3岁前癫痫的20%，因此是一个主要的临床负担。在这些患者中可以发现先天性代谢错误、脑部病变或遗传缺陷。尽管过去进行了国际上的努力和大规模的外显子组研究，但只有少数遗传EEs能够被澄清。原因是(a)关注经典EEs，如Lennox-Gastaut和West综合征，(b)强调对新生突变的分析，(c)对非经典EEs的小队列的限制，如目前由DFG资助的三人EE项目，该项目正在进一步探索非典型EE表型。因此，在本提案中，对基因表达的遗传机制的分析将扩展到对现有国际基因表达外显子组数据集的联合分析，目标如下：(i)针对各种遗传模式（新生、隐性、x染色体）对约1800例经典EEs和非典型EEs的患者-亲本三组进行全队列外显子组分析；（ii）根据现有外显子组数据对EE患者的新生和其他罕见变异进行分析；（iia）根据Z2和P5-P7项目的RNA测序结果或P2和P3项目中新出现的候选基因和表达数量性状位点（eqtl）进行优先排序；（iib）与P2和P3合作，重新分析表观遗传调控因子；（iic）与P2合作，利用遗传和转录数据，基于基因网络，将其整合到EE癫痫发生的疾病模型中；（iii）对检测到的新遗传变异进行功能分析。该项目将建立一个全面的EE基因和易感因素遗传网络，这将导致癫痫发生模型的改进，并为该疾病组的系统、精准医学方法奠定基础

Epileptic encephalopathies (EEs) are childhood-onset, therapy resistant epilepsies accompanied by developmental delay and various other comorbidities such as ataxia or dystonia. Collectively, the EEs account for up to 20% of all epilepsies starting before the age of 3 years, thus representing a major clinical burden. Inborn errors of metabolism, brain lesions or genetic defects can be identified in these patients. Despite international efforts and large-scale exome studies in the past, only a minority of genetic EEs could be clarified. Reasons were (a) the focus on classical EEs such as Lennox-Gastaut and West syndrome, (b) the emphasis of the analysis on de novo mutations, (c) the limitation on small cohorts in non-classical EEs such as the ongoing trio EE project currently funded by the DFG, which is venturing into further, atypical EE phenotypes. Therefore, within this proposal the analysis of the genetic mechanisms of EE will be extended to a joint analysis of available international exome EE datasets with the following objectives: (i) cohort-wide exome analysis on ca. 1800 patient-parent trios of classical and atypical EEs for various inheritance models (de novo, recessive, x-chromosomal), (ii) analysis of de novo and other rare variants in EE patients in existing exome data (iia) prioritized by results from RNA sequencing from projects Z2 & P5-P7 or with respect to emerging candidate genes and expression quantitative trait loci (eQTLs) from projects P2 & P3, (iib) re-analyzed with respect to epigenetic regulators in collaboration with P2 & P3 and (iic) integrated into a disease model for EE epileptogenesis based on gene networks using genetic and transcriptional data in collaboration with P2, and (iii) functional analysis of detected novel genetic variants. The project will lead to a comprehensive genetic network of genes and susceptibility factors for EE which will lead to a refinement of epileptogenesis models and form the basis for a systematic, precision medicine approach in this disease group