Analysis of monogenic essential Tremor by exome sequencing.

原发性震颤（ET）是第二常见的运动障碍，在一般人群中的终生患病率>1%。基尔大学的神经病学系和我的研究所是ET临床、病理生理学和遗传学研究的领先中心。 在临床上，ET的特征在于姿势性震颤，此外还经常是在严重情况下使人衰弱的运动性震颤。ET的病理生理基础在很大程度上是未知的。提出脑干中产生异常振荡活动的功能性假说与神经退行性假说相竞争。在大多数情况下，ET是遗传复杂的，具有高遗传性。在之前的项目中，我们对ET进行了全基因组关联研究（GWAS），并确定了主要谷氨酸再摄取转运蛋白（SLC1A2）的遗传风险变体。与图宾根大学、因斯布鲁克大学和维也纳大学合作的第二个规模更大的GWAS将很快完成。在少数情况下ET的遗传模式是兼容的常染色体显性遗传。传统的遗传学方法如连锁分析等尚不能揭示单基因ET的病因。这种失败的原因可能是缺乏许多非常大的家庭，表型模仿，减少遗传率和基因座异质性。一个ET候选基因（融合在肉瘤，FUS）的单基因ET最近已被确定的外显子组测序。鉴定导致单基因ET的其他遗传变异是极其重要的，因为常见疾病的单基因形式通常是其常见多基因对应物的病理机制的宝贵模型。我们与来自奥地利、德国和法国的研究小组合作，对56个有三个或三个以上成员明确受ET影响的家庭进行了研究。外显子组测序是一种强有力的方法，以确定致病突变的单基因疾病，如果大量的家庭进行了分析，并适用于适当的变异过滤策略。大量的家庭将确定致病基因，即使在高基因座异质性的存在。通过与基尔大学临床分子生物学研究所（IKMB）的联合提案，将保证卓越的技术测序质量，最先进的生物信息学和有竞争力的价格，该研究所拥有德国最大的下一代测序设施之一。我们的工作组已经在外显子组测序项目中获得了已发表的经验，并使用传统的基于连锁的方法鉴定了单基因疾病的新基因。我们有信心，我们的项目将确定一个或多个基因暗示在ET的发病机制。

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.