Background

Next-generation sequencing has become a first-line tool for the diagnosis of primary immunodeficiency. However, patient access remains limited because of restricted insurance coverage and a lack of guidelines addressing the use of targeted panels versus whole-exome sequencing (WES).

Objectives

We sought to compare targeted next-generation sequencing with WES in a global population of patients with primary immunodeficiency.

Methods

This was a longitudinal study of 878 patients with likely primary immunodeficiency sequenced between 2010 and 2020. Most patients (n = 780) were first sequenced using a 264 gene panel. This was followed by WES in selected cases if a candidate gene was not found. A subset of patients (n = 98) were selected for a WES-only pipeline if the history was atypical for genes within the targeted panel.

Results

Disease-causing variants were identified in 498 of the 878 probands (56%), encompassing 152 distinct monogenic disorders. Sixteen patients had disorders that were novel at the time of sequencing (1.8%). Diagnostic yield in patients sequenced by targeted panel was 56% (433 of 780 patients), with subsequent WES leading to an additional 18 diagnoses (overall diagnostic yield 58%, 451 of 780 patients). The WES-only approach had a diagnostic yield of 45% (45 of 98 patients), reflecting that these cases had less common clinical and laboratory phenotypes. Cost analysis, based on current commercial WES and targeted panel prices, demonstrated savings ranging from $300 to $950 with a WES-only approach, depending on diagnostic yield.

Conclusions

Advantages of WES over targeted next-generation sequencing include simplified workflow, reduced overall cost, and the potential for identification of novel diseases.

中文翻译：

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在 878 例疑似原发性免疫缺陷患者中，靶向 panel 与全外显子组测序的疗效和经济性

背景

二代测序已成为诊断原发性免疫缺陷的一线工具。然而，由于保险范围有限以及缺乏针对使用靶向 panel 与全外显子组测序 (WES) 的指南，患者的访问仍然有限。

目标

我们试图在全球原发性免疫缺陷患者群体中比较靶向二代测序与 WES。

方法

这是一项纵向研究，对 2010 年至 2020 年间可能患有原发性免疫缺陷的 878 名患者进行了测序。大多数患者（n = 780）首先使用 264 基因组进行测序。如果未找到候选基因，则在选定的情况下进行 WES。如果目标面板中基因的历史不典型，则选择一部分患者（n = 98）用于仅 WES 管道。

结果

在 878 名先证者中的 498 名（56%）中发现了致病变异，包括 152 种不同的单基因疾病。16 名患者在测序时患有新疾病（1.8%）。通过靶向组测序的患者的诊断率为 56%（780 名患者中的 433 名），随后的 WES 导致另外 18 名诊断（总体诊断率 58%，780 名患者中的 451 名）。仅 WES 方法的诊断率为 45%（98 名患者中的 45 名），反映出这些病例的临床和实验室表型不太常见。基于当前商业 WES 和目标面板价格的成本分析表明，仅 WES 方法可节省 300 至 950 美元，具体取决于诊断产量。

结论

WES 优于靶向二代测序的优势包括简化工作流程、降低总体成本以及识别新疾病的潜力。