A semiautomated whole-exome sequencing workflow leads to increased diagnostic yield and identification of novel candidate variants
A semiautomated whole-exome sequencing workflow leads to increased diagnostic yield and identification of novel candidate variants
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DOI：
10.1101/mcs.a003756
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发表时间：
2019-04-01
影响因子：
1.8
通讯作者：
Gai, Xiaowu
中科院分区：
文献类型：
--
作者：
Ji, Jianling;Shen, Lishuang;Gai, Xiaowu
推进全外显子组测序（WES）在疑似遗传性疾病患者中的临床应用主要是由简化数据处理和分析的生物信息学方法驱动的。在此，我们描述了我们在一家拥有不同种族儿科患者人群的学术儿童医院实施半自动化和表型驱动的WES诊断工作流程的经验，该工作流程结合了DRAGEN管道和Exomiser变体优先排序工具。我们对66例双、四或三重WES病例的分子诊断率为41%，对40例单重WES病例的分子诊断率为28%。初步结果返回订购医生在1周内为12 38（32%）先证者的阳性结果，这是有助于指导适当的临床管理的各种患者，特别是在重症监护环境。半自动化和简化的WES工作流程还使我们能够识别发育迟缓和自闭症以及免疫疾病和癌症患者的候选疾病基因中的新变体，包括ANK2，BPTF，BCL 11A，FOXN1，PLAA，ATRX，DNAJC 21和RAD 50。我们一起展示了一个精简的WES工作流程的实施，该工作流程成功地应用于临床和研究目的。
Advancing the clinical utility of whole-exome sequencing (WES) for patients with suspected genetic disorders is largely driven by bioinformatics approaches that streamline data processing and analysis. Herein, we describe our experience with implementing a semiautomated and phenotype-driven WES diagnostic workflow, incorporating both the DRAGEN pipeline and the Exomiser variant prioritization tool, at an academic children's hospital with an ethnically diverse pediatric patient population. We achieved a 41% molecular diagnostic rate for 66 duo-, quad-, or trio-WES cases, and 28% for 40 singleton-WES cases. Preliminary results were returned to ordering physicians within 1 wk for 12 of 38 (32%) probands with positive findings, which were instrumental in guiding the appropriate clinical management for a variety of patients, especially in critical care settings. The semiautomated and streamlined WES workflow also enabled us to identify novel variants in candidate disease genes in patients with developmental delay and autism and immune disorders and cancer, including ANK2, BPTF, BCL11A, FOXN1, PLAA, ATRX, DNAJC21, and RAD50. Together, we demonstrated the implementation of a streamlined WES workflow that was successfully applied for both clinical and research purposes.