Molecular phenotyping of ~100,000 coding variants across Mendelian disease genes

摘要 在过去的四十年里，人类基因组变异产生了巨大的目录， 来彻底改变人类基因在迄今为止在人类“变异组”中鉴定出的变异中， 良性，即它们似乎不赋予任何特定的表型，很大一部分是相关的， 可能与一种或多种遗传性疾病有关，但更大比例的 观察到的人类变异，99%的错义变异，仍然未被解释或注释为未知的变异， 显著性（VUS）。将这些巨大的遗传信息转化为 基因型-表型关系以及负责遗传性疾病发展的分子机制 疾病，迫切需要大规模，系统，高通量的“功能表征” 新的“基因组变异对功能的影响”（IGVF）联盟中设想的项目 由NHGRI提出。 虽然大多数单基因孟德尔疾病是个别罕见的，当这些疾病合并影响20 数百万美国人ClinVar数据库描述了超过260，000个孟德尔疾病基因， 错义变体被分类为致病的、良性的或VUS。我们目前缺乏强大和全面的 这是系统分析人类孟德尔疾病谱中编码变异的证据。 我们建议在大多数已知的孟德尔疾病中对约100，000种变体进行功能表征- 通过比较野生型或“参考”基因产物及其相应的变体， 丰富的基本蛋白质特性和表型影响，包括蛋白质稳定性（表达）， 亚细胞定位、细胞活力、细胞形态以及介导大分子与 蛋白质伴侣 我们的孟德尔蛋白质组变异特征（VarChAMP）中心将生成一个可搜索的 并通过IGVF数据和行政协调中心广泛提供这些变异效应的目录 （DACCs），并协助“预测建模项目”，使用 这些数据。除了提供关于数以万计的基因组变异的功能信息的丰富来源之外 在未来五年内，我们在该项目中产生的所有概念、技术和资源都可以出口 并将共享，以使IGVF联盟内外的其他人能够利用我们的方法， 他们自己的研究和扩大目录。

Abstract The last four decades have produced an enormous catalog of human genomic variants which has the potential to revolutionize human genetics. Among the variants identified in the human “variome” so far, some appear benign, i.e. they don’t seem to confer any particular phenotype, a significant proportion are associated or potentially associated with one or more genetically inherited disorders, but an even greater percentage of observed human variants, 99% of missense variants, remain uninterpreted or annotated as variants of unknown significance (VUSs). To translate this huge amount of genetic information into general principles underlying genotype-phenotype relationships as well as molecular mechanisms responsible for the development of inherited disease, there is an urgent need for large-scale, systematic, high throughput “functional characterization” projects such as those envisioned within the new “Impact of Genomic Variation on Function” (IGVF) Consortium proposed by NHGRI. Although most monogenic Mendelian disorders are individually rare, when combined these diseases affect 20 million Americans. The ClinVar database describes within 3,671 Mendelian disease genes over 260,000 missense variants classified as pathogenic, benign, or VUSs. We currently lack strong and comprehensive evidence to systematically analyze coding variants across the spectrum of human Mendelian diseases. We propose to functionally characterize ~100,000 variants across most of the known Mendelian disease- associated genes by comparing wild-type, or “reference”, gene products and their corresponding variants for a rich array of fundamental protein properties and phenotypic impacts, including protein stability (expression), subcellular localization, cell viability, cell morphology, and the ability to mediate macromolecular interactions with protein partners. Our Variant Characterization Across the Mendelian Proteome (VarChAMP) Center will generate a searchable and widely available catalog of these variant effects via the IGVF Data and Administrative Coordinating Centers (DACCs), and assist in the “Predictive Modeling Projects” to carry out variant effect predictive modeling using this data. In addition to providing a rich source of functional information on tens of thousands of genomic variants in the next five years, all of our concepts, technologies and resources generated during this project are exportable and will be shared to enable others, both inside and outside the IGVF consortium, to leverage our approach in their own studies and expand the catalog.