Purpose

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.

Methods

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.

Results

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.

Conclusion

Integration of translational research activities into clinical practice of a tertiary medical center can significantly increase the diagnostic yield of patients with undiagnosed disease.

中文翻译：

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整合转化研究对临床外显子组测序的影响

目的

外显子组测序通常可以识别未确诊疾病患者的致病性遗传变异。然而，频繁发现具有不确定意义的变异，需要在得出结论性诊断之前进一步努力建立因果关系。为了向未确诊疾病的患者提供全面的基因组测试，我们建立了一个个体化医学诊所，提供临床外显子组测试，并包括一个转化组学计划 (TOP)，提供变异管理、研究活动或研究外显子组测序。

方法

从 2012 年到 2018 年，1101 名未经选择的未确诊疾病患者接受了外显子组检测。通过描述性和多变量分析对结果进行审查，以评估 TOP 和患者特征对诊断率的影响。

结果

总体诊断率为 24.9%（1101 名患者中的 274 名），仅根据临床外显子组测序诊断出 174 名（1101 名患者中的 15.8%）。TOP 评估了 423 名未诊断或无法获得临床外显子组测序的患者，其中 100 名（1101 名患者中的 9%）接受了诊断，占诊断率的 36.5%。基因诊断的鉴定受测试时的年龄和患者的疾病表型影响。

结论

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着提高未确诊疾病患者的诊断率。