Division of Anatomic and Molecular Pathology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri.
Division of Laboratory and Genomic Medicine, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri.
Kidney360. 2020 May 13;1(8):772-780. doi: 10.34067/KID.0001342020. eCollection 2020 Aug 27.
BACKGROUND: Next-generation sequencing (NGS) is a useful tool for evaluating patients with suspected genetic kidney disease. Clinical practice relies on the use of targeted gene panels that are ordered based on patient presentation. We compare the diagnostic yield of clinical panel-based testing to exome analysis. METHODS: In total, 324 consecutive patients underwent physician-ordered, panel-based NGS testing between December 2014 and October 2018. Gene panels were available for four clinical phenotypes, including atypical hemolytic uremic syndrome (=224), nephrotic syndrome (=56), cystic kidney disease (=26), and Alport syndrome (=13). Variants were analyzed and clinical reports were signed out by a pathologist or clinical geneticist at the time of testing. Subsequently, all patients underwent retrospective exome analysis to detect additional clinically significant variants in kidney disease genes that were not analyzed as part of the initial clinical gene panel. Resulting variants were classified according to the American College of Medical Genetics and Genomics 2015 guidelines. RESULTS: In the initial physician-ordered gene panels, we identified clinically significant pathogenic or likely pathogenic variants in 13% of patients (=42/324). homozygous deletion was detected in an additional 13 patients with aHUS without a pathogenic or likely pathogenic variant. Diagnostic yield of the initial physician-ordered gene panel was 20% and varied between groups. Retrospective exome analysis identified 18 patients with a previously unknown pathogenic or likely pathogenic variant in a kidney disease gene and eight patients with a high-risk genotype. Overall, retrospective exome analysis increased the diagnostic yield of panel-based testing from 20% to 30%. CONCLUSIONS: These results highlight the importance of a broad and collaborative approach between the clinical laboratory and their physician clients that employs additional analysis when a targeted panel of kidney disease-causing genes does not return a clinically meaningful result.
背景：下一代测序（NGS）是评估疑似遗传性肾脏疾病患者的有用工具。临床实践依赖于基于患者表现的靶向基因panel 的使用。我们比较了基于临床panel 的检测和外显子分析的诊断效果。
方法：总共 324 名连续患者在 2014 年 12 月至 2018 年 10 月期间进行了医师指令的、基于 panel 的 NGS 检测。基因panel 可用于四种临床表型，包括非典型溶血尿毒症综合征（=224）、肾病综合征（=56）、囊性肾脏疾病（=26）和 Alport 综合征（=13）。在测试时，通过病理学家或临床遗传学家对变体进行分析和临床报告签字。随后，所有患者均进行了回顾性外显子分析，以检测初始临床基因 panel 中未分析的肾脏疾病基因中的其他具有临床意义的变体。根据美国医学遗传学和基因组学学院 2015 年的指南对变体进行分类。
结果：在初始的医师指令的基因 panel 中，我们在 13%的患者（=42/324）中鉴定出具有临床意义的致病性或可能致病性变体。在没有致病性或可能致病性变体的 aHUS 患者中，还检测到了 13 例纯合缺失。初始医师指令的基因 panel 的诊断效果为 20%，且在各小组之间存在差异。回顾性外显子分析鉴定出了 18 名患者具有肾脏疾病基因中先前未知的致病性或可能致病性变体和 8 名患者具有高风险 基因型。总体而言，回顾性外显子分析将基于 panel 的检测的诊断效果从 20%提高到 30%。
结论：这些结果强调了临床实验室与其医师客户之间广泛而协作的方法的重要性，当靶向肾脏疾病致病基因 panel 未产生有临床意义的结果时，需要采用额外的分析方法。
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