Genomic Studies in Charcot-Marie-Tooth Disease

腓骨肌萎缩症的基因组研究

基本信息

批准号：
10018118
负责人：
MICHAEL E. SHY
金额：
$ 63.11万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-15 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10018118
关键词：
Address Advanced Development Affect Alleles Alternative Splicing Asia Assimilations Axon Brazil Candidate Disease Gene Case-Control Studies Charcot-Marie-Tooth Disease Clinic Clinical Clinical Data Clinical Trials Code Collaborations Collection Custom DNA Data Data Analyses Databases Deposition Development Diagnosis Disease Elements Enrollment Evaluation Familial Amyloidosis Family Functional disorder Generations Genes Genetic Genetic study Genomic approach Genomics Genotype Goals Grant Hereditary Disease Hereditary Motor and Sensory Neuropathy Type I Hereditary Motor and Sensory-Neuropathy Type II Individual Infrastructure Inherited International Investigation Lebanon Methods Morocco Motor Neurons Nerve Degeneration Neurology Neuromuscular Diseases Neurons Neuropathy North America Oligogenic Traits Pathogenicity Pathway Analysis Pathway interactions Patients Peripheral Nerves Peripheral Nervous System Diseases Peru Phenotype Proteins Publishing RNA Splicing Rare Diseases Research Personnel Resources Sampling Site South America South Korea Spinal Muscular Atrophy Standardization Structure Technology Thailand Time Untranslated RNA Variant Work base clinical database data sharing database of Genotypes and Phenotypes digital exome exome sequencing follow-up gene therapy genetic architecture genetic disorder diagnosis genetic testing genome sequencing giant axonal neuropathy in silico induced pluripotent stem cell innovation insight network models novel rare variant recruit risk variant success tool transcriptome sequencing whole genome

项目摘要

PROJECT SUMMARY The various forms of Charcot-Marie-Tooth disease (CMT) comprise a genetically heterogeneous set of peripheral neuropathies. Currently >90 different CMT genes have been identified; yet, for the axonal CMT2 subtype these genes explain only 30-40% of the genetic effect. Especially the application of exome sequencing has led to an unprecedented pace in identifying about half of those genes in the past five years. We have been at the forefront of this development with 22+ published new gene identifications in the past seven years. This success was only possible through broad national and international collaborations, data sharing, and the development of advanced analysis tools and methods. We also learned that despite exome sequencing, over 50% of axonal CMT patients remain undiagnosed pointing towards even more genes; however, our preliminary data also support the existence of non- coding variation as Mendelian allele contributor. In this grant we will continue our highly impactful work in CMT family recruitment, exome sequencing and traditional gene identification. In addition, we will expand the genetic studies to whole genome sequencing with a focus on families already explored unsuccessfully in whole exome studies. We further plan to perform the first large rare variant burden analysis in the rare disorder CMT2 – this is only possibly through the exceptional clinical resources we have built over the past decade. Finally, with many CMT genes available, we will perform statistical network analyses on a CMT-ome to identify gene modules and pathways that will be the starting point of polypharmacology and provide insight into pathophysiology of peripheral nerve degeneration. All data will be available in real-time to an existing network of CMT investigators worldwide, and deposited in dbGAP annually. !

项目概要各种形式的腓骨肌萎缩症 (CMT) 包括一组遗传异质性的疾病目前已鉴定出超过 90 种不同的 CMT 基因；对于轴突 CMT2 这些基因亚型只能解释30-40%的遗传效应，尤其是外显子组测序的应用。在过去的五年里，我们以前所未有的速度识别了其中大约一半的基因。在过去七年中发表了 22 多个新基因鉴定，处于这一发展的最前沿。只有通过广泛的国家和国际合作、数据共享以及我们还了解到，尽管外显子组测序已经结束。然而，50% 的轴突 CMT 患者仍未得到诊断，这表明有更多的基因；数据还支持非编码变异作为孟德尔等位基因贡献者的存在。继续我们在 CMT 家族招募、外显子组测序和传统基因方面极具影响力的工作此外，我们还将把遗传学研究扩展到全基因组测序，重点是全基因组测序。家庭已经在全外显子组研究中探索失败，我们进一步计划进行第一次大型罕见的研究。罕见疾病 CMT2 中的变异负荷分析——这只能通过特殊的临床研究来实现最后，我们将利用过去十年积累的许多 CMT 基因来进行。对 CMT-ome 进行统计网络分析，以确定将成为起始的基因模块和途径多药理学观点并提供对周围神经变性病理生理学的深入了解所有数据。将实时提供给全球 CMT 研究人员的现有网络，并存入 dbGAP 每年。！