A powerful web-based discovery platform for rare disease genetics

项目摘要 人类疾病遗传学的一个基本挑战是分离出少数变异， 与疾病表型无关的绝大多数变异体构成疾病表型的基础。 尽管面临这一挑战，但由于 事实上，它们主要是由单个基因中的功能变体丧失引起的， DNA测序的技术进步。然而，尽管取得了许多成功， 数以千计的孟德尔疾病仍然是未知的，数百个新的孟德尔疾病被描述 每年.此外，在所研究的孟德尔疾病中，只有不到一半的疾病在测序后得到解决。 受影响的家庭。 根据我们在诊断罕见疾病和开发研究软件方面的经验， 域，我们认为，现有的商业工具是不够的和昂贵的。研究管道， 罕见疾病需要大量的计算专业知识和整合不同的基因组注释 以及用于变体优先化的算法。这种管道的技术复杂性阻碍了发现， 研究人员具有丰富的疾病知识，但有限的计算资源或经验。因此，我们认为， 我们的目标是构建一个可扩展、交互式、最先进的软件平台，使流程民主化 基因发现在孟德尔和其他罕见疾病的研究。我们的第一个目标是创造 GxBrowse：一个用于罕见疾病发现的开源互动平台， GEMINI、xBrowse和Exome Aggregation Consortium，这三个广泛使用的工具和资源 在我们的实验室里开发的。其次，我们将最大限度地提高GxBrowse的性能、可伸缩性， 促进未来罕见疾病研究的可及性，特别是随着该领域的研究从 外显子组到全基因组测序。最后，我们将为变体提供创新策略， 解释，可视化和数据共享，以显着提高诊断率和基因 的发现 GxBrowse平台将解决基因发现中的基本分析挑战， 孟德尔疾病，并为罕见疾病分析提供强大且可扩展的开源工具包 广泛的研究人员都能接触到。我们预计，GxBrowse将使许多研究实验室， 对于NIH资助的大型研究项目（如孟德尔遗传学中心）的未来发现来说， 基因组学和未诊断疾病网络。

PROJECT SUMMARY A fundamental challenge in human disease genetics is separating the small minority of variants that underlie a disease phenotype from the overwhelming majority of variants that are irrelevant to the phenotype. Resolving the genetic basis of rare diseases has been relatively fruitful despite this challenge, thanks to the fact that they are primarily caused by loss of function variants in a single gene and to the tremendous technological advances in DNA sequencing. However, despite many successes, the genetic basis of thousands of Mendelian disorders remains unknown and hundreds of new Mendelian disorders are described each year. Moreover, less than half of the Mendelian disorders studied are resolved after sequencing of affected families. Based on our experience in diagnosing rare diseases and in developing research software in this domain, we argue that existing commercial tools are both inadequate and expensive. Research pipelines for rare disease require substantial computational expertise and the integration of diverse genome annotations and algorithms for variant prioritization. The technical complexity of such pipelines inhibits discovery from researchers with substantial disease knowledge yet limited computational resources or experience. Therefore, our goal is to build a scalable, interactive, state-of-the-art software platform that will democratize the process of gene discovery in studies of Mendelian and other rare diseases. Our first Specific Aim is to create GxBrowse: an open source, interactive platform for rare disease discovery, drawing on the strengths of GEMINI, xBrowse, and the Exome Aggregation Consortium, three widely used tools and resources developed in our laboratories. Secondly, we will maximize GxBrowse’s performance, scalability, and accessibility to facilitate future rare disease research, especially as research in this area transitions from exome to whole genome sequencing. Lastly, we will provide innovative strategies for variant interpretation, visualization and data sharing to dramatically increase the rate of diagnosis and gene discovery. The GxBrowse platform will address fundamental analytical challenges in gene discovery for rare Mendelian diseases, and make a powerful and scalable open-source toolkit for rare disease analysis accessible to a wide range of researchers. We anticipate that GxBrowse will empower many research labs and become invaluable to future discoveries in larger NIH-funded efforts such as the Centers for Mendelian Genomics and the Undiagnosed Diseases Network.