Autosomal recessive (AR) complete signal transducer and activator of transcription 1 (STAT1) deficiency is an extremely rare primary immunodeficiency that causes life-threatening mycobacterial and viral infections. Only seven patients from five unrelated families with this disorder have been so far reported. All causal STAT1 mutations reported are exonic and homozygous. We studied a patient with susceptibility to mycobacteria and virus infections, resulting in identification of AR complete STAT1 deficiency due to compound heterozygous mutations, both located in introns: c.128+2 T>G and c.542-8 A>G. Both mutations were the first intronic STAT1 mutations to cause AR complete STAT1 deficiency. Targeted RNA-seq documented the impairment of STAT1 mRNA expression and contributed to the identification of the intronic mutations. The patient’s cells showed a lack of STAT1 expression and phosphorylation, and severe impairment of the cellular response to IFN-γ and IFN-α. The case reflects the importance of accurate clinical diagnosis and precise evaluation, to include intronic mutations, in the comprehensive genomic study when the patient lacks molecular pathogenesis. In conclusion, AR complete STAT1 deficiency can be caused by compound heterozygous and intronic mutations. Targeted RNA-seq-based systemic gene expression assay may help to increase diagnostic yield in inconclusive cases after comprehensive genomic study.

中文翻译：

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由复合杂合内含子突变引起的常染色体隐性完全 STAT1 缺陷。

常染色体隐性 (AR) 完全信号转导和转录激活因子 1 (STAT1) 缺陷是一种极为罕见的原发性免疫缺陷，可导致危及生命的分枝杆菌和病毒感染。迄今为止，仅报告了来自五个无关家庭的七名患有这种疾病的患者。报告的所有因果STAT1突变都是外显子和纯合子。我们研究了一名对分枝杆菌和病毒感染易感的患者，由于复合杂合突变，两者都位于内含子：c.128+2 T>G 和 c.542-8 A>G，因此鉴定出 AR 完全 STAT1 缺陷。这两个突变都是第一个导致 AR 完全 STAT1 缺乏的内含子STAT1突变。靶向 RNA-seq 记录了STAT1的损伤mRNA 表达并有助于鉴定内含子突变。患者的细胞显示缺乏 STAT1 表达和磷酸化，并且对 IFN-γ 和 IFN-α 的细胞反应严重受损。该病例反映了当患者缺乏分子发病机制时，在综合基因组研究中准确临床诊断和精确评估的重要性，包括内含子突变。总之，AR完全STAT1缺陷可由复合杂合子和内含子突变引起。在综合基因组研究后，基于靶向 RNA-seq 的系统性基因表达测定可能有助于提高不确定病例的诊断率。