Lim Euyn, Borden Chloe, Mehta Seysha, Roberts Mary-Beth, Mazzola Sarah, Zhao Fang, Wang Xiangling
Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA.
Kidney Int Rep. 2024 Feb 6;9(5):1441-1450. doi: 10.1016/j.ekir.2024.01.055. eCollection 2024 May.
Genetic testing is increasingly utilized in nephrology practice, but limited real-world data exist on variant reclassification following renal genetics testing.
A cohort of patients at the Cleveland Clinic Renal Genetics Clinic who underwent genetic testing through clinical laboratories was assessed with their clinical and laboratory data analyzed.
Between January 2019 and June 2023, 425 new patients with variable kidney disorders from 413 pedigrees completed genetic testing through 10 clinical laboratories, including 255 (60%) females with median (25th, 75th percentiles) age of 36 (22-54) years. Multigene panel was the most frequently used modality followed by single-gene testing, exome sequencing (ES), chromosomal microarray (CMA), and genome sequencing (GS). At initial report, 52% of patients had ≥1 variants of uncertain significance (VUS) with or without concurrent pathogenic variant(s). Twenty amendments were issued across 19 pedigrees involving 19 variants in 17 genes. The overall variant reclassification rate was 5%, with 63% being upgrades and 32% downgrades. Of the reclassified variants, 79% were initially reported as VUS. The median time-to-amendments from initial reports was 8.4 (4-27) months. Following the variant reclassifications, 60% of the patients received a new diagnosis or a change in diagnosis. Among these, 67% of patients received significant changes in clinical management.
Variant reclassification following genetic testing is infrequent but important for diagnosis and management of patients with suspected genetic kidney disease. The majority of variant reclassifications involve VUS and are upgrades in clinically issued amended reports. Further studies are needed to investigate the predictors of such events.
基因检测在肾脏病学实践中的应用日益广泛，但关于肾脏基因检测后变异重新分类的真实世界数据有限。
对克利夫兰诊所肾脏基因诊所中通过临床实验室进行基因检测的一组患者进行评估，并分析其临床和实验室数据。
在2019年1月至2023年6月期间，来自413个家系的425例患有各种肾脏疾病的新患者通过10个临床实验室完成了基因检测，其中包括255例（60%）女性，年龄中位数（第25、75百分位数）为36（22 - 54）岁。多基因检测是最常用的方式，其次是单基因检测、外显子组测序（ES）、染色体微阵列（CMA）和基因组测序（GS）。在初始报告中，52%的患者有≥1个意义未明的变异（VUS），伴有或不伴有同时存在的致病变异。在19个家系中发布了20项修订，涉及17个基因中的19个变异。总体变异重新分类率为5%，其中63%为升级，32%为降级。在重新分类的变异中，79%最初被报告为VUS。从初始报告到修订的中位时间为8.4（4 - 27）个月。在变异重新分类后，60%的患者获得了新诊断或诊断改变。其中，67%的患者临床管理发生了重大变化。
基因检测后的变异重新分类并不常见，但对疑似遗传性肾病患者的诊断和管理很重要。大多数变异重新分类涉及VUS，并且在临床发布的修订报告中为升级。需要进一步研究来调查此类事件的预测因素。
