Viapath Genetics Laboratories, Guy's Hospital, London, United Kingdom; Department of Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom.
Department of Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom; Birmingham Health Partners, Birmingham Women's and Children's Hospital NHS Trust, Birmingham, United Kingdom.
Genet Med. 2022 Apr;24(4):811-820. doi: 10.1016/j.gim.2021.11.021. Epub 2021 Nov 27.
This study aimed to investigate whether a bioinformatics application can streamline genome reanalysis and yield new diagnoses for patients with rare diseases.
We developed TierUp to identify variants in new disease genes for unresolved rare disease cases recruited to the 100,000 Genomes Project, all of whom underwent genome sequencing. TierUp uses the NHS Genomic Medicine Service bioinformatics infrastructure by securely accessing case details from the Clinical Interpretation Portal application programming interface and by querying the curated PanelApp database for novel gene-disease associations. We applied TierUp to 948 cases, and a subset of variants were reclassified according to the American College of Medical Genetics and Genomics/Association of Molecular Pathology guidelines.
A rare form of spondylometaphyseal dysplasia was diagnosed through TierUp reanalysis, and an additional 4 variants have been reported to date. From a total of 564,441 variants across patients, TierUp highlighted 410 variants present in novel disease genes in under 77 minutes, successfully expediting an important reanalysis strategy.
TierUp supports claims that automation can reduce the time taken to reanalyze variants and increase the diagnostic yield from molecular testing. Clinical services should leverage bioinformatics expertise to develop tools that enable routine reanalysis. In addition, services must also explore the ethical, legal, and health economic considerations raised by automation.
本研究旨在探讨生物信息学应用程序是否可以简化基因组再分析，并为罕见病患者提供新的诊断。
我们开发了 TierUp，以识别 100,000 基因组计划中招募的未解决的罕见病病例中未解决的新疾病基因中的变异，所有这些病例都进行了基因组测序。TierUp 通过安全地从临床解释门户应用程序编程接口访问病例详细信息，并通过查询经过审核的 PanelApp 数据库来查询新的基因-疾病关联，利用国民保健制度基因组医学服务的生物信息学基础设施。我们将 TierUp 应用于 948 例病例，并且根据美国医学遗传学和基因组学学院/分子病理学协会的指南对部分变体进行了重新分类。
通过 TierUp 重新分析诊断出一种罕见形式的脊椎骨骺发育不良，并且迄今为止已报告了另外 4 种变体。在患者的总共 564,441 个变体中，TierUp 在不到 77 分钟的时间内突出显示了 410 个存在于新疾病基因中的变体，成功地加速了重要的重新分析策略。
TierUp 支持自动化可以减少重新分析变体所需的时间并提高分子测试的诊断产量的说法。临床服务应利用生物信息学专业知识来开发工具，以实现常规重新分析。此外，服务部门还必须探讨自动化带来的伦理、法律和健康经济方面的考虑。
