An Improved Phenotype-Driven Tool for Rare Mendelian Variant Prioritization: Benchmarking Exomiser on Real Patient Whole-Exome Data
An Improved Phenotype-Driven Tool for Rare Mendelian Variant Prioritization: Benchmarking Exomiser on Real Patient Whole-Exome Data
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DOI：
10.3390/genes11040460
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发表时间：
2020-04-01
期刊：
影响因子：
3.5
通讯作者：
Smedley, Damian
中科院分区：
文献类型：
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作者：
Cipriani, Valentina;Pontikos, Nikolas;Smedley, Damian
新一代测序已经彻底改变了罕见疾病的诊断，但许多患者仍然没有得到分子诊断，特别是因为许多候选变异通常在严格过滤的情况下存活下来。Exomiser于2014年作为Java工具推出，用于对患者测序数据及其用人类表型本体（HPO）术语编码的表型进行综合分析。它通过利用变异频率、预测致病性和源自人类疾病、模式生物和蛋白质-蛋白质相互作用的基因-表型关联等信息，对变异进行优先排序。早期发布的Exomiser能够在高达97%的模拟全外显子组中优先考虑致病变异作为首选候选。迄今为止发表的经过测试的真实患者数据集的规模非常有限。在这里，我们介绍具有许多新特性的最新Exomiser 12.0.1版本。我们使用来自一系列罕见视网膜疾病患者的134个全外显子组和已知的分子诊断来评估其性能。使用默认设置，Exomiser在74%的数据集中将正确诊断的变体列为首选，在94%的数据集中排名前5；不使用患者的HPO谱（即，仅变量分析）将性能分别降低到3%和27%。总之，Exomiser是罕见的孟德尔表型驱动的变异优先排序的有效支持工具。
Next-generation sequencing has revolutionized rare disease diagnostics, but many patients remain without a molecular diagnosis, particularly because many candidate variants usually survive despite strict filtering. Exomiser was launched in 2014 as a Java tool that performs an integrative analysis of patients' sequencing data and their phenotypes encoded with Human Phenotype Ontology (HPO) terms. It prioritizes variants by leveraging information on variant frequency, predicted pathogenicity, and gene-phenotype associations derived from human diseases, model organisms, and protein-protein interactions. Early published releases of Exomiser were able to prioritize disease-causative variants as top candidates in up to 97% of simulated whole-exomes. The size of the tested real patient datasets published so far are very limited. Here, we present the latest Exomiser version 12.0.1 with many new features. We assessed the performance using a set of 134 whole-exomes from patients with a range of rare retinal diseases and known molecular diagnosis. Using default settings, Exomiser ranked the correct diagnosed variants as the top candidate in 74% of the dataset and top 5 in 94%; not using the patients' HPO profiles (i.e., variant-only analysis) decreased the performance to 3% and 27%, respectively. In conclusion, Exomiser is an effective support tool for rare Mendelian phenotype-driven variant prioritization.