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

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。 接近了。后者需要对每个患者进行精确的基因诊断，遗传学也将是 对长期结果具有很高的信息量。然而，即使鉴定出90多个CMT和相关基因，超过 50%的CMT2患者今天没有得到诊断。这种遗传力的差距有很多潜在的可能。 解释，包括待发现的其他CMT基因，非编码突变，非常规 变异(即重复扩增)、寡基因遗传和未知意义的变异。我们的长期合作 致力于CMT1a的遗传修饰物研究已经产生了全基因组范围的显著关联 SIPA1L2为第一个CMT1a修饰基因。重要的是，这一发现承诺了一种新的战略来 纠正PMP22基因剂量的增加。该公司已经收集了1700名CMT1A患者的样本和 预计未来五年还会有1000人。用新的统计方法和基因组测序 现在，我们将结合所有这些优势和优势，充分发挥这一无与伦比的努力的潜力 全面定义了CMT1a的基因结构。我们预计，其中一些风险因素具有 对其他更常见类型的CMT的影响，例如CMT1B、CMTX和CMT2A。在过去的资金 期间，我们已经发现了22+个新的CMT和相关基因，包括导致重复扩增的CMT 疾病。我们将继续这项工作，但重点是改进我们的样本和数据资源的大小和 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。我们将开发一个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，在前一个筹资周期中，我们 我创建了遗传性神经病变异浏览器(INVB)来收集CMT中与疾病相关的变异 并向社区公开提供这方面的信息。鉴于我们对以下方面的特殊兴趣 CMT和相关疾病以及我们的国际覆盖范围，这项以CMT为重点的努力远远超出了 NIH ClinVar.我们将开发包含更多数据、更多关联和更深层次的INVB 2.0版 关于VUS的信息。具体地说，我们建议(1)进行迭代扩展的修饰物研究 CMT1a和其他相对常见的CMT亚型，(2)为数据共享和 继续发现新的CMT基因，以及(3)开发CMT变体浏览器2.0，它还将提供 CMT表型库使患者和研究人员能够快速获得诊断和识别 有关疾病导致突变的临床信息。

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.