颜林林
(2022-06-19 00:14):
#paper doi:10.1186/s13073-022-01069-z Genome Medicine, 2022, Reanalysis of exome negative patients with rare disease: a pragmatic workflow for diagnostic applications. 过去这些年里，我们经常会对罕见遗传病患者开展全外显子组测序，以便确认其致病基因并形成诊断结论。然而，受限于技术和积累的知识，大部分患者在测序后也仍然无法确诊。这篇来自荷兰拉德堡德大学（Radboud University）的文章，回顾了其医学中心在2011年11月至2015年1月期间到访的疑似罹患复杂神经系统遗传疾病的150名儿童患者，对其中103名未得到确诊的患者进行了随访调查，通过重新查阅评估表型信息、重新分析其全外显子测序数据，以及对仍无法确诊的患者（使用新的实验流程和外显子panel）重新进行测序和分析。这一系列操作，让32名之前未被诊断的患者得到确诊，诊断率从31%（47/150）提升到53%（79/150）。其结果也支持了在临床护理和后续随访过程中，应该对未确诊患者进行重新分析和系统评估，新的临床证据信息、新的技术方法和分析方法，都有助于改善诊治，使患者获益。
Reanalysis of exome negative patients with rare disease: a pragmatic workflow for diagnostic applications
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Abstract:
BACKGROUND: Approximately two third of patients with a rare genetic disease remain undiagnosed after exome sequencing (ES). As part of our post-test counseling procedures, patients without a conclusive diagnosis are advised to recontact their referring clinician to discuss new diagnostic opportunities in due time. We performed a systematic study of genetically undiagnosed patients 5 years after their initial negative ES report to determine the efficiency of diverse reanalysis strategies.METHODS: We revisited a cohort of 150 pediatric neurology patients originally enrolled at Radboud University Medical Center, of whom 103 initially remained genetically undiagnosed. We monitored uptake of physician-initiated routine clinical and/or genetic re-evaluation (ad hoc re-evaluation) and performed systematic reanalysis, including ES-based resequencing, of all genetically undiagnosed patients (systematic re-evaluation).RESULTS: Ad hoc re-evaluation was initiated for 45 of 103 patients and yielded 18 diagnoses (including 1 non-genetic). Subsequent systematic re-evaluation identified another 14 diagnoses, increasing the diagnostic yield in our cohort from 31% (47/150) to 53% (79/150). New genetic diagnoses were established by reclassification of previously identified variants (10%, 3/31), reanalysis with enhanced bioinformatic pipelines (19%, 6/31), improved coverage after resequencing (29%, 9/31), and new disease-gene associations (42%, 13/31). Crucially, our systematic study also showed that 11 of the 14 further conclusive genetic diagnoses were made in patients without a genetic diagnosis that did not recontact their referring clinician.CONCLUSIONS: We find that upon re-evaluation of undiagnosed patients, both reanalysis of existing ES data as well as resequencing strategies are needed to identify additional genetic diagnoses. Importantly, not all patients are routinely re-evaluated in clinical care, prolonging their diagnostic trajectory, unless systematic reanalysis is facilitated. We have translated our observations into considerations for systematic and ad hoc reanalysis in routine genetic care.
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