Analysis of monogenic essential Tremor by exome sequencing.

特发性震颤（ET）是普通人群中第二大最常见的运动障碍，其终生患病率为1%。基尔大学的神经内科和我的工作小组是ET临床、病理生理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，通常还会出现动态性震颤，严重的时候会使人虚弱。ET的病理生理基础在很大程度上是未知的。一个功能假说提出异常振荡活动产生的脑干与神经退行性假说竞争。ET在大多数情况下是遗传复杂的，具有很高的遗传性。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）的遗传风险变异。与<s:1>宾根大学、因斯布鲁克大学和维也纳大学合作的第二个更大的GWAS即将完工。在少数ET病例中，遗传模式与常染色体显性遗传相容。传统的遗传策略，如连锁分析，无法揭示单基因ET的原因。导致这种失败的原因可能是缺乏大量的非常大的家族、表型、外显率降低和位点异质性。最近通过外显子组测序发现了一个单基因ET的候选基因（融合在肉瘤中，FUS）。鉴定引起单基因ET的其他遗传变异非常重要，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。与来自奥地利、德国和法国的研究小组合作，我们研究了56个有三个或更多成员明确受到ET影响的家庭。如果分析大量家庭并采用适当的变异过滤策略，外显子组测序是识别单基因疾病中引起疾病突变的有力方法。大量的家庭将确定致病基因，即使在存在高位点异质性。通过与基尔大学临床分子生物学研究所（IKMB）的联合提案，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将得到保证，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公开发表的经验，并使用传统的基于连锁的方法确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.