Identification of epilepsy genes through family studies in the Middle East

癫痫是一种常见的中枢神经系统疾病，具有很强的遗传影响。然而，大多数易感遗传因素仍然难以捉摸。到目前为止，孟德尔类型癫痫的分析一直是癫痫遗传学中最成功的领域，到目前为止，已发现20多个与单基因癫痫有关的基因。虽然过去的遗传分析仅限于大家庭，但基于大规模并行测序的新技术现在可以在较小的单基因家庭中进行基因鉴定。在过去的两年里，已经出现了癫痫和神经发育障碍的基因识别的新浪潮。在单基因疾病负担特别沉重的社区进行精简的招募程序，再加上通过新技术对遗传风险因素进行系统评估，为大规模基因鉴定开辟了可能性。与许多其他西方国家相比，以色列和巴勒斯坦的家庭规模更大，血缘关系更密切。此外，一个完善的卫生保健系统允许获取详细的临床数据、神经生理学和神经成像。因此，对中东家族性癫痫的研究为发现新的癫痫基因提供了难得的机会。在这项赠款提案中，我们将包括过去24个月在以色列和巴勒斯坦利用已建立的招募渠道招募的100个家庭和291名受影响的个人。对于来自巴勒斯坦的家庭，我们还建立了表型工作流程，允许受影响的家庭成员进行脑电和神经成像，确保在巴勒斯坦卫生保健系统不那么全面的地区也能进行高质量的表型分析。我们的提案包括三个主要单元，将在24个月内完成。在模块A中，将按等级顺序对100个招募的表型家系进行遗传筛选，包括(1)使用基因面板分析排除突出的候选基因，(2)全基因组连锁分析以缩小与疾病相关的基因组区域，以及(3)用于疾病变异识别的完整外显子组测序。在模块B中，我们将通过对临床或研究背景下测序的3000名癫痫患者的外显组/基因组数据进行全面的数据挖掘，筛选出更多具有已识别基因突变的患者。在单元C中，我们将在两年内再招募100个家庭，并使用基因板筛选这些家庭新发现的候选基因的额外突变。

The epilepsies are common disorders of the Central Nervous System with a strong genetic impact. However, most of the predisposing genetic factors remain elusive. The analysis of Mendelian forms of epilepsy has so far been the most successful field in epilepsy genetics and to date, more than 20 genes implicated in monogenic epilepsies have been identified. While the genetic analysis was limited to large families in the past, novel technologies based on massive parallel sequencing now allow for gene identification in smaller, monogenic families. Already, the last two years have seen a new wave of gene identification in epilepsies and neurodevelopmental disorders. A streamlined recruitment pipeline in communities with a particularly strong burden of monogenic diseases in combination with a systematic assessment of genetic risk factors through novel technologies opens up the possibility for large-scale gene identification. In contrast to many other Western countries, families in Israel and Palestine are larger and have a higher degree of consanguinity. In addition, a well-developed health care system allows for the acquisition of detailed clinical data, neurophysiology and neuroimaging. Therefore, investigation of familial epilepsies in the Middle East provides a unique opportunity for the discovery of novel epilepsy genes. In this grant proposal we will include 100 families with 291 affected individuals, who have been recruited in the last 24 months in Israel and Palestine, taking advantage of an established recruitment pipeline. For families from Palestine, we have also established a phenotyping workflow that allows affected family members to have EEG and neuroimaging performed, guaranteeing high-quality phenotyping also in areas of Palestine where the health care system is less comprehensive. Our proposal consists of three major modules to be completed in a period of 24 months. In Module A, genetic screening will be performed in 100 recruited and phenotyped families in a hierarchical order including (1) exclusion of prominent candidate genes using gene panel analysis, (2) genome-wide linkage analysis to narrow down disease associated genomic regions and (3) Whole Exome Sequencing for disease variant identification. In Module B, we will screen for additional patients with mutations in identified genes through a comprehensive data mining of exome/genome data of >3000 epilepsy patients sequenced in a clinical or research context. In Module C, we will recruit 100 additional families within a two year period and screen these families for additional mutations of the newly identified candidate genes using gene panels.