Analysis of monogenic essential Tremor by exome sequencing.

• Applicants: Professor Dr. Günther Deuschl; Professor Dr. Andre Franke; Professor Gregor Kuhlenbäumer, Ph.D.
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Human Genetics ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2014 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 258890088

Essential Tremor (ET) is with a lifetime prevalence of >1% in the general population the second most common movement disorder. The Department of Neurology and my workgroup at the University of Kiel are a leading center for the clinical, pathophysiological and genetic investigation of ET. Clinically, ET is characterized by a postural and in addition often also a kinetic tremor which is debilitating in severe cases. The pathophysiologic basis of ET is largely unknown. A functional hypothesis proposing abnormal oscillatory activity generated in the brain stem competes with a neurodegenerative hypothesis. ET is in most cases genetically complex with a high heritability. In the preceding project we performed a genome wide association study (GWAS) for ET and identified genetic risk variants in the major glutamate reuptake transporter (SLC1A2). A second, much larger GWAS in cooperation with the universities of Tübingen, Innsbruck and Vienna will soon be finished. In a minority of cases ET the inheritance pattern is compatible with autosomal dominant inheritance. Conventional genetic strategies like linkage-analysis have not been able to reveal the causes of monogenic ET. Among the causes for this failure might be the lack of numerous very large families, phenocopies, reduced penetrance and locus-heterogeneity. One ET-candidate gene (fused in sarcoma, FUS) for monogenic ET has recently been identified by exome sequencing. The identification of additional genetic variants causing monogenic ET is extremely important because monogenic forms of common disease are often invaluable models for the pathomechanism of their common polygenic counterparts. In cooperation with groups from Austria, Germany and France we have examined 56 families with three or more members definitively affected by ET. Exome sequencing is a powerful method to identify disease causing mutations in monogenic disorders if large numbers of families are analyzed and appropriate variant filtering strategies are applied. The large number of families will identify causative genes even if in the presence of high locus heterogeneity. Excellent technical sequencing quality, state of the art bioinformatics and competitive pricing will be guaranteed through this joint proposal together with the Institute of Clinical Molecular Biology (IKMB) at the University of Kiel which houses one of the largest Next-Generation-Sequencing facilities in Germany. Our workgroups have already gained published experience in exome sequencing projects and have identified novel genes for monogenic disorders using conventional linkage based approaches. We are confident, that our project will identify one or more genes implied in the pathogenesis of ET.

• DFG Programme: Research Grants