Identification of epilepsy genes through family studies in the Middle East

• Applicant: Professor Dr. Ingo Helbig
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: from 2014 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 245609332

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.

• DFG Programme: Research Grants
• International Connection: Israel, Palestine
• International Co-Applicants: Professor Dr. Zaid Afawi, Ph.D.; Professor Dr. Moien Kanaan, Ph.D.