Identifying genetic factors that cause and modify CMT (Project 2)

识别导致和改变 CMT 的遗传因素（项目 2）

• 批准号: 10456929
• 负责人: Stephan Zuchner
• 金额: $ 34.76万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10456929
• 关键词: Address; Alleles; Bioinformatics; Case Study; ClinVar; Clinical; Clinical Treatment; Collaborations; Communities; Computer software; DNA; Data; Data Set; Diagnosis; Diagnostic; Disease; Family; FarGo; Functional disorder; Funding; Gene Dosage; Genes; Genetic; Genetic Research; Genomic medicine; Genomics; Genotype; Hereditary Motor and Sensory-Neuropathy Type II; Heritability; Infrastructure; International; Laboratories; Link; Mutation; Natural History; Neurologist; Neuromuscular Diseases; Neuropathy; Oligogenic Traits; Outcome; Outcome Measure; PMP22 gene; Patients; Phenotype; Preparation; Research Personnel; Risk Factors; Sampling; Statistical Data Interpretation; Statistical Methods; Technology; Testing; United States National Institutes of Health; Untranslated RNA; Variant; Work; data archive; data infrastructure; data resource; data sharing; disease-causing mutation; gene discovery; gene therapy; genetic architecture; genetic disorder diagnosis; genome sequencing; genome wide association study; genome-wide; hereditary neuropathy; improved; individual patient; interest; international center; novel; novel strategies; outcome prediction; outreach; protective allele; success; targeted treatment; training opportunity; trial design; variant of unknown significance; virtual; whole genome

Abstract Genetics is at the core of CMT diagnoses, pathophysiology, and preparation for trials and gene therapy approaches. The latter requires precise genetic diagnosis for each individual patient and genetics will also be highly informative for long-term outcomes. However, even with 90+ CMT and related genes identified, over 50% of CMT2 patients do not receive a diagnosis today. This gap in heritability has many potential explanations, including additional CMT genes to be discovered, non-coding mutations, unconventional variation (i.e. repeat expansions), oligogenic inheritance, and Variants of Unknown Significance. Our long-term commitment to the genetic modifier study in CMT1A has yielded a genome wide significant association (GWAS) of SIPA1L2 as the first CMT1A modifier gene. Importantly, this discovery promises a novel strategy to correct the increased gene dosage of PMP22. The INC has collected 1,700 samples of CMT1A patients and another 1,000 are expected over the next five years. With new statistical methods and genome sequencing now available we will bring this unparalleled effort to its full potential by combining all these strengths and comprehensively define the genetic architecture of CMT1A. We anticipate that some of these risk factors have effects on other more common types of CMT, such as CMT1B, CMTX, and CMT2A. Over the past funding period, we have discovered 22+ novel CMT and related genes, including a CMT causing repeat expansion disease. We will continue this work, but focus on improving our sample and data resources in size and ancestral diversity. This will be achieved by further expanding data sharing with CMT-ID, AOINC, and the MRC in the UK. We will develop a CMT genetic data archive and utilize the GENESIS genomic software platform that has helped to discover most of the above mentioned CMT genes. Finally, in the previous funding cycle we have created the Inherited Neuropathy Variant Browser (INVB) to collect disease related variation in CMT genes internationally and provide this information openly to the community. Given our specialized interest in CMT and related disorders and our international reach, this CMT-focused effort goes far beyond the reach of NIH ClinVar. We will develop INVB version 2.0 that includes more data, additional correlations, and deeper information on VUS. Specifically, we propose to (1) Perform an Iterative expansion of modifier studies in CMT1A and other relatively common CMT subtypes, (2) Build a sustained infrastructure for data sharing and continued discovery of new CMT genes, and (3) Develop the CMT variant browser 2.0 that will also provide a phenotype bank for CMT enabling patients and investigators to rapidly obtain diagnostic and de-identified clinical information on disease causing mutations.

摘要 遗传学是CMT诊断、病理生理学以及试验和基因治疗准备的核心 接近。后者需要对每个患者进行精确的基因诊断，遗传学也将被 对长期结果非常有用。然而，即使有90多个CMT和相关基因被鉴定出来， 50%的CMT 2患者今天没有得到诊断。遗传力的这种差距有很多潜力 解释，包括额外的CMT基因被发现，非编码突变，非常规 变异（即重复扩增）、寡基因遗传和意义未知的变异。我们的长期 致力于CMT 1A的遗传修饰剂研究已经产生了基因组范围内的显著关联， （GWAS）将SiPA 1 L2作为第一个CMT 1A修饰基因。重要的是，这一发现预示着一种新的策略， 纠正PMP 22基因剂量的增加。INC已经收集了1,700份CMT 1A患者的样本， 预计今后五年内将再增加1,000个。用新的统计方法和基因组测序 现在，我们将把所有这些优势结合起来， 全面定义CMT 1A的遗传结构。我们预计，其中一些风险因素 对其他更常见类型的CMT的影响，如CMT 1B，CMTX和CMT 2A。在过去的融资 在此期间，我们已经发现了22个新的CMT和相关基因，包括一个引起重复扩增的CMT 疾病我们将继续这项工作，但重点是提高我们的样本和数据资源的规模， 祖先的多样性这将通过进一步扩大与CMT-ID、AOINC和MRC的数据共享来实现 在英国我们将开发CMT遗传数据档案，并利用GENESIS基因组软件平台 这有助于发现上述大多数CMT基因。最后，在上一个供资周期， 我创建了遗传性神经病变异浏览器（INVB），以收集CMT中与疾病相关的变异 基因在国际上，并提供这一信息公开给社会。考虑到我们对 CMT和相关疾病以及我们的国际影响力，这种以CMT为重点的努力远远超出了 NIH ClinVar.我们将开发INVB 2.0版，其中包括更多的数据，额外的相关性，以及更深入的 关于VUS的信息具体来说，我们建议（1）对修饰剂研究进行迭代扩展， CMT 1A和其他相对常见的CMT亚型，（2）建立持续的数据共享基础设施， 继续发现新的CMT基因，以及（3）开发CMT变体浏览器2.0，该浏览器还将提供 CMT的表型库，使患者和研究者能够快速获得诊断和去识别 关于致病突变的临床信息。