Identification of epilepsy genes through family studies in the Middle East

癫痫是中枢神经系统的常见疾病，具有强烈的遗传影响。然而，大多数诱发遗传因素仍然难以捉摸。孟德尔形式癫痫的分析是迄今为止癫痫遗传学中最成功的领域，迄今为止，已经鉴定出20多个与单基因癫痫有关的基因。虽然过去遗传分析仅限于大家族，但基于大规模平行测序的新技术现在允许在较小的单基因家族中进行基因鉴定。在过去的两年里，癫痫和神经发育障碍的基因鉴定已经出现了新的浪潮。在单基因疾病负担特别重的社区建立精简的招募渠道，再加上通过新技术对遗传风险因素进行系统评估，为大规模基因鉴定提供了可能性。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，发达的医疗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，在中东的家族性癫痫的调查提供了一个独特的机会，发现新的癫痫基因。在这项赠款提案中，我们将包括100个家庭和291名受影响的个人，他们在过去24个月内在以色列和巴勒斯坦被招募，利用既定的招募渠道。对于来自巴勒斯坦的家庭，我们还建立了一个表型鉴定工作流程，允许受影响的家庭成员进行脑电图和神经成像，确保在巴勒斯坦医疗保健系统不太全面的地区也能进行高质量的表型鉴定。我们的建议包括三个主要模块，将在24个月内完成。在模块A中，将在100个招募和表型分型的家族中按分层顺序进行遗传筛查，包括（1）使用基因组分析排除突出的候选基因，（2）全基因组连锁分析以缩小疾病相关基因组区域，以及（3）全外显子组测序以鉴定疾病变体。在模块B中，我们将通过对临床或研究背景下测序的>3000名癫痫患者的外显子组/基因组数据进行全面数据挖掘，筛选在已鉴定基因中具有突变的其他患者。在模块C中，我们将在两年内招募100个额外的家庭，并使用基因面板筛选这些家庭中新发现的候选基因的其他突变。

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.