Purpose

Owing to recent technological advancements, using next-generation sequencing (NGS) and the accumulation of clinical experiences worldwide, more than 420 genes associated with inborn errors of immunity (IEI) have been identified, which exhibit large genotypic and phenotypic variations. Consequently, NGS-based comprehensive genetic analysis, including whole-exome sequencing (WES), have become more valuable in the clinical setting and have contributed to earlier diagnosis, improved treatment, and prognosis. However, these approaches have the following disadvantages that need to be considered: a relatively low diagnostic rate, high cost, difficulties in the interpretation of each variant, and the risk of incidental findings. Thus, the objective of this study is to review our WES results of a large number of patients with IEI and to elucidate patient characteristics, which are related to the positive WES result.

Methods

We performed WES for 136 IEI patients with negative conventional screening results for candidate genes and classified these variants depending on validity of their pathogenicity.

Results

We identified disease-causing pathogenic mutations in 36 (26.5%) of the patients which were found in known IEI-causing genes. Although the overall diagnostic rate was not high and was not apparently correlated with the clinical subcategories and severity, we revealed that earlier onset with longer duration of diseases were associated with positive WES results, especially in pediatric cases.

Conclusions

Most of the disease-causing germline mutations were located in the known IEI genes which could be predicted using patients’ clinical characteristics. These results may be useful when considering appropriate genetic approaches in the clinical setting.

中文翻译：

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基于全外显子组测序的先天免疫缺陷患者种系突变的方法。

目的

由于最近的技术进步，使用新一代测序（NGS）和全球临床经验的积累，已经鉴定了 420 多个与先天性免疫缺陷（IEI）相关的基因，这些基因表现出较大的基因型和表型变异。因此，基于 NGS 的综合遗传分析，包括全外显子组测序 (WES)，在临床环境中变得更有价值，并有助于早期诊断、改善治疗和预后。然而，这些方法有以下需要考虑的缺点：诊断率相对较低、成本高、每个变异的解释困难以及偶然发现的风险。因此，

方法

我们对 136 名 IEI 患者进行了 WES，其候选基因的常规筛查结果为阴性，并根据其致病性的有效性对这些变异进行分类。

结果

我们在 36 名 (26.5%) 的患者中发现了致病的致病突变，这些突变在已知的 IEI 致病基因中发现。虽然总体诊断率不高，并且与临床亚类和严重程度没有明显的相关性，但我们发现早期发病和疾病持续时间较长与阳性 WES 结果相关，尤其是在儿科病例中。

结论

大多数致病种系突变位于已知的 IEI 基因中，可以使用患者的临床特征进行预测。在临床环境中考虑适当的遗传方法时，这些结果可能有用。