Analysis of monogenic essential Tremor by exome sequencing.

特发性震颤(ET)在普通人群中的终生患病率为1%，是第二种最常见的运动障碍。基尔大学神经病学系和我的工作组是ET临床、病理生理学和遗传学研究的领先中心。临床上，ET的特征是体位性震颤，此外，经常还会出现运动性震颤，严重时会使人虚弱。ET的病理生理学基础在很大程度上还不清楚。提出脑干产生异常振荡活动的功能假说与神经退行性假说相竞争。ET在大多数情况下是遗传复杂的，具有很高的遗传力。在前面的项目中，我们对ET进行了全基因组关联研究，并确定了主要谷氨酸再摄取转运体(SLC1A2)的遗传风险变异。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GWA项目即将竣工。少数病例的遗传方式符合常染色体显性遗传。传统的遗传策略，如连锁分析，已经不能揭示单基因ET的原因。这一失败的原因之一可能是缺乏许多非常大的家庭、表型、外显率降低和基因座异质性。最近通过外显子测序鉴定了一个ET候选基因(融合在肉瘤中，FUS)，它与单基因ET有关。识别引起单基因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往往是其常见多基因对应疾病的致病机制的宝贵模型。与来自奥地利、德国和法国的小组合作，我们检查了56个有三个或三个以上成员明确受到ET影响的家庭。如果对大量家系进行分析并应用适当的变异筛选策略，外显子组测序是鉴定单基因疾病致病突变的有效方法。即使在存在高度基因异质性的情况下，大量的家系也会识别致病基因。出色的技术测序质量、最先进的生物信息学和具有竞争力的定价将通过与基尔大学临床分子生物学研究所(IKMB)的联合提案得到保证。基尔大学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识别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与ET发病机制有关的基因。

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.