Elucidating and understanding the genetic basis of movement disorders

描述(由申请人提供)： 复杂运动障碍(CMD)是指患者受到一种以上运动障碍(如帕金森症和肌张力障碍，或肌阵挛和震颤)的影响，是诊断和治疗的持续挑战。CMDS通常是进行性的，阻止患者执行基本的日常功能，如行走、进食和说话，并导致患者及其家人与疾病相关的高经济和个人负担。此外，已知的与运动障碍基因相关的表型和病原学异质性是相当惊人的，对治疗提出了重大挑战。因此，早期诊断对于合理治疗以恢复运动能力和提高患者的生活质量至关重要。由于运动障碍(MD)的遗传学研究在发现潜在的病理过程方面取得了成功，并帮助研究人员了解了疾病的表现和进展，因此识别MDS发生的潜在或促成的遗传因素为理解其相关的病理提供了强有力的工具。因此，为了识别与这些CMD相关的分子网络并促进新的治疗，该建议侧重于招募家族性和散发性的CMD患者，并识别他们的致病等位基因。因为整个外显子组测序(WES)已经证明了它能够识别遗传病的致病等位基因，即使在以前被认为具有统计学意义的家系中也是如此 对于位置克隆能力不足，并且已经成为孟德尔和更复杂性状的基因鉴定的一种卓有成效的策略，WES与基于SNP的阵列一起将在本提案中用于致病突变鉴定，该阵列将减少对因果变异的搜索。我们相信，对这些疾病的深入研究是阐明CMDs和更常见的疾病(如帕金森氏病)的发病机制的有效途径，并将导致诊断和治疗的改进。综上所述，本研究将有助于发现新的CMD基因及其表型特征，这不仅对于了解CMD的病因和病理生理学是必不可少的，而且对于开发更有针对性和更有效的治疗策略也将对人类健康大有裨益。

DESCRIPTION (provided by applicant): Complex movement disorders (CMDs), defined as disorders in which patients are affected by more than one movement disorder (such as parkinsonism and dystonia, or myoclonus and tremor), are a continuing challenge for diagnosis and treatment. CMDs are usually progressive, prevent patients from performing basic daily functions such as walking, eating, and talking, and result in high disease-associated financial and personal burden for patients and their families. Moreover, the already-known phenotypic and etiologic heterogeneity associated with movement disorder genes is quite striking and presents a significant challenge for treatment. Therefore, early diagnosis is crucial for appropriate treatment to restore motor activities and improve patients' quality of life. Since genetic studies in movement disorders (MDs) have demonstrated their success in the discovery of underlying pathologic processes and have helped researchers to understand both disease manifestation and progression, the identification of genetic factors underlying, or contributing to, the development of MDs provides a powerful tool for understanding their associated pathology. Accordingly, in an attempt to identify molecular networks associated with these CMDs and to facilitate novel treatments, this proposal focuses on the recruitment of familial and sporadic patients with CMDs, and the identification of their disease-causing alleles. Because whole exome sequencing (WES) has proved its ability to identify causative alleles for inherited diseases, even in families previously deemed statistically underpowered for positional cloning, and has become a fruitful strategy for gene identification in both Mendelian and more complex traits, WES, along with SNP-based arrays, which will reduce the search for causal variants, will be used for disease- causing mutation identification in this proposal. We believe that intense study of these disorders represents a powerful approach to elucidate disease mechanism for both CMDs and for more common disorders such as Parkinson's disease, and will lead to improvements in both diagnoses and treatments. In conclusion, this study will contribute enormously to the identification of novel CMD genes and the characterization of their phenotype, which not only are essential for understanding the etiology and pathophysiology of CMDs, but also for developing more targeted and efficient therapeutic strategies that will be of great benefit to human health.