Background

Combined immunodeficiencies (CIDs) are diseases of defective adaptive immunity with diverse clinical phenotypes. Although CIDs are more prevalent in the Middle East than Western countries, the resources for genetic diagnosis are limited.

Objectives

This study aims to characterize the categories of patients with CIDs in Iran clinically and genetically.

Methods

Clinical and laboratory data were obtained from 696 patients with CIDs. Patients were subdivided into those with syndromic (344 patients) and nonsyndromic (352 patients) CIDs. Targeted DNA sequencing was performed on 243 (34.9%) patients.

Results

The overall diagnostic yield of the 243 sequenced patients was 77.8% (189 patients). The clinical diagnosis of hyper-IgE syndrome (P < .001), onset of disease at greater than 5 years (P = .02), and absence of multiple affected family members (P = .04) were significantly more frequent in the patients without a genetic diagnosis. An autosomal recessive disease was found in 62.9% of patients, reflecting the high rate of consanguinity in this cohort. Mutations impairing VDJ recombination and DNA repair were the most common underlying causes of CIDs. However, in patients with syndromic CIDs, autosomal recessive mutations in ataxia-telangiectasia mutated (ATM), autosomal dominant mutations in signal transducer and activator of transcription 3 (STAT3), and microdeletions in 22q11.21 were the most commonly affected genomic loci. Patients with syndromic CIDs had a significantly lower 5-year survival rate rather than those with nonsyndromic CIDs.

Conclusions

This study provides proof of principle for the application of targeted next-generation sequencing panels in countries with limited diagnostic resources. The effect of genetic diagnosis on clinical care requires continued improvements in therapeutic resources for these patients.

中文翻译：

---

696例合并免疫缺陷患者的临床，免疫学和基因谱

背景

组合免疫缺陷（CID）是适应性免疫缺陷的疾病，具有多种临床表型。尽管CID在中东比西方国家更普遍，但是用于基因诊断的资源有限。

目标

这项研究的目的是在临床和遗传上表征伊朗CID患者的类别。

方法

临床和实验室数据来自696名CID患者。将患者分为具有综合症状的（344例）和非综合症状的（352例）CID。针对243名（34.9％）患者进行了靶向DNA测序。

结果

243例经测序的患者的总诊断率为77.8％（189例患者）。患者中高IgE综合征的临床诊断（P  <.001），发病超过5年（P  = .02）和缺少多个受影响的家庭成员（P  = .04）的发生率明显更高没有基因诊断。在62.9％的患者中发现了常染色体隐性遗传疾病，这反映出该人群的血缘病发生率很高。损害VDJ重组和DNA修复的突变是CID的最常见根本原因。但是，在具有综合症CID的患者中，共济失调-毛细血管扩张突变（ATM）的常染色体隐性突变，信号转导和转录激活子3 （STAT3）的常染色体显性突变以及22q11.21中的微缺失是最常见的基因组位点。具有综合症状CID的患者的5年生存率明显低于没有综合症状CID的患者。

结论

这项研究为在诊断资源有限的国家中应用靶向的下一代测序专家组提供了原理证明。遗传诊断对临床护理的影响要求持续改善这些患者的治疗资源。