Identification of rare-disease genes using blood transcriptome sequencing and large control cohorts
Identification of rare-disease genes using blood transcriptome sequencing and large control cohorts
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DOI：
10.1038/s41591-019-0457-8
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发表时间：
2019-06-01
期刊：
影响因子：
82.9
通讯作者：
Dyment, David
中科院分区：
文献类型：
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作者：
Fresard, Laure;Smail, Craig;Dyment, David
据估计，全世界有3.5亿人患有罕见疾病，这些疾病主要是由单个基因突变引起的（1）。目前的分子诊断率估计为50%，全外显子组测序（WES）是最成功的方法之一（2-5）。对于WES无信息的患者，RNA测序（RNA-seq）已显示出在特定组织和疾病中的诊断实用性（6-8）。这包括未确诊的罕见肌肉疾病患者的肌肉活检（6，9），以及线粒体疾病患者的培养成纤维细胞（7）。然而，对于许多个体而言，活检不是为了临床护理而进行的，并且组织难以接近。我们试图评估来自血液的RNA-seq作为不同病理生理学罕见疾病的诊断工具的效用。我们从94名患有未诊断的罕见疾病的个体中产生了全血RNA-seq，这些疾病跨越16种不同的疾病类别。我们开发了一种强大的方法来比较这些个体的数据与对照组的大型RNA-seq数据集（n = 1，594个无关对照和n = 49个家庭成员），并证明了表达，剪接，基因和变异过滤策略对疾病基因识别的影响。在我们的队列中，我们观察到RNA-seq产生了7.5%的诊断率，另外还有16.7%的候选基因分辨率提高。
It is estimated that 350 million individuals worldwide suffer from rare diseases, which are predominantly caused by mutation in a single gene(1). The current molecular diagnostic rate is estimated at 50%, with whole-exome sequencing (WES) among the most successful approaches(2-5). For patients in whom WES is uninformative, RNA sequencing (RNA-seq) has shown diagnostic utility in specific tissues and diseases(6-8). This includes muscle biopsies from patients with undiagnosed rare muscle disorders(6,9), and cultured fibroblasts from patients with mitochondrial disorders(7). However, for many individuals, biopsies are not performed for clinical care, and tissues are difficult to access. We sought to assess the utility of RNA-seq from blood as a diagnostic tool for rare diseases of different pathophysiologies. We generated whole-blood RNA-seq from 94 individuals with undiagnosed rare diseases spanning 16 diverse disease categories. We developed a robust approach to compare data from these individuals with large sets of RNA-seq data for controls (n = 1,594 unrelated controls and n = 49 family members) and demonstrated the impacts of expression, splicing, gene and variant filtering strategies on disease gene identification. Across our cohort, we observed that RNA-seq yields a 7.5% diagnostic rate, and an additional 16.7% with improved candidate gene resolution.