Department of Health Sciences Research, College of Medicine, Mayo Clinic, Rochester, MN, USA.
Center for Individualized Medicine, College of Medicine, Mayo Clinic, Rochester, MN, USA.
Genet Med. 2021 Mar;23(3):498-507. doi: 10.1038/s41436-020-01005-9. Epub 2020 Nov 4.
Exome sequencing often identifies pathogenic genetic variants in patients with undiagnosed diseases. Nevertheless, frequent findings of variants of uncertain significance necessitate additional efforts to establish causality before reaching a conclusive diagnosis. To provide comprehensive genomic testing to patients with undiagnosed disease, we established an Individualized Medicine Clinic, which offered clinical exome testing and included a Translational Omics Program (TOP) that provided variant curation, research activities, or research exome sequencing.
From 2012 to 2018, 1101 unselected patients with undiagnosed diseases received exome testing. Outcomes were reviewed to assess impact of the TOP and patient characteristics on diagnostic rates through descriptive and multivariate analyses.
The overall diagnostic yield was 24.9% (274 of 1101 patients), with 174 (15.8% of 1101) diagnosed on the basis of clinical exome sequencing alone. Four hundred twenty-three patients with nondiagnostic or without access to clinical exome sequencing were evaluated by the TOP, with 100 (9% of 1101) patients receiving a diagnosis, accounting for 36.5% of the diagnostic yield. The identification of a genetic diagnosis was influenced by the age at time of testing and the disease phenotype of the patient.
Integration of translational research activities into clinical practice of a tertiary medical center can significantly increase the diagnostic yield of patients with undiagnosed disease.
外显子组测序经常在患有不明疾病的患者中鉴定出致病性遗传变异。然而，经常发现意义不明的变异需要在得出明确诊断之前进行额外的努力来确定因果关系。为了向患有不明疾病的患者提供全面的基因组检测，我们建立了个体化医学诊所，提供临床外显子组检测，并包括一个提供变异分类、研究活动或研究外显子组测序的转化组学计划 (TOP)。
从 2012 年到 2018 年，1101 名患有不明疾病的未经选择的患者接受了外显子组检测。通过描述性和多变量分析，回顾了检测结果，以评估 TOP 和患者特征对诊断率的影响。
总体诊断率为 24.9%（1101 例患者中有 274 例），仅基于临床外显子组测序诊断的有 174 例（1101 例的 15.8%）。423 例无诊断或无法进行临床外显子组测序的患者接受了 TOP 的评估，其中 100 例（1101 例的 9%）患者得到了诊断，占诊断率的 36.5%。遗传诊断的确定受检测时的年龄和患者的疾病表型的影响。
将转化研究活动整合到三级医疗中心的临床实践中可以显著提高患有不明疾病的患者的诊断率。
