Abstract：
We described the diagnosis and treatment of a patient with autoinflammatory disease, named \"Deficiency in ELF4, X-linked (DEX)\". A novel ELF4 variant was discovered and its pathogenic mechanism was elucidated. The data about clinical, laboratory and endoscopic features, treatment, and follow-up of a patient with DEX were analyzed. Whole exome sequencing and Sanger sequencing were performed to identify potential pathogenic variants. The mRNA and protein levels of ELF4 were analyzed by qPCR and Western blotting, respectively. The association of ELF4 frameshift variant with nonsense-mediated mRNA decay (NMD) in the pathogenesis DEX was examined. Moreover, RNA-seq was performed to identify the key molecular events triggered by ELF4 variant. The relationship between ELF4 and IFN-β activity was validated using a dual-luciferase reporter assay and a ChIP-qPCR assay. An 11-year-old boy presented with a Behçet\'s-like phenotype. The laboratory abnormality was the most obvious in elevated inflammatory indicators. Endoscopy revealed multiple ileocecal ulcers. Intestinal histopathology showed inflammatory cell infiltrations. The patient was treated with long-term immunosuppressant and TNF-α blocker (adalimumab), which reaped an excellent response over 16 months of follow-up. Genetic analysis identified a maternal hemizygote frameshift variant (c.1022del, p.Q341Rfs*30) in ELF4 gene in the proband. The novel variant decreased the mRNA level of ELF4 via the NMD pathway. Mechanistically, insufficient expression of ELF4 disturbed the immune system, leading to immunological disorders and pathogen susceptibility, and disrupted ELF4-activating IFN-β responses. This analysis detailed the clinical characteristics of a Chinese patient with DEX who harbored a novel ELF4 frameshift variant. For the first time, we used patient-derived cells and carried out transcriptomic analysis to delve into the mechanism of ELF4 variant in DEX.
摘要：
我们描述了自身炎性疾病患者的诊断和治疗，名为“ELF4缺乏，X连锁(DEX)”。发现了一种新的ELF4变体，并阐明了其致病机理。关于临床的数据，实验室和内窥镜特征，治疗,并对1例DEX患者的随访情况进行分析。进行全外显子组测序和Sanger测序以鉴定潜在的致病变体。通过qPCR和Western印迹分析ELF4的mRNA和蛋白水平,分别。研究了ELF4移码变体与无义介导的mRNA衰减（NMD）在DEX发病机理中的关联。此外，进行RNA-seq以鉴定由ELF4变体触发的关键分子事件。使用双荧光素酶报告基因测定和ChIP-qPCR测定验证了ELF4和IFN-β活性之间的关系。一个11岁的男孩表现出类似Behçet的表型。实验室异常以炎症指标升高最为明显。内窥镜检查显示多个回盲部溃疡。肠组织病理学显示炎性细胞浸润。患者接受长期免疫抑制剂和TNF-α受体阻滞剂（阿达木单抗）治疗，在16个月的随访中获得了极好的反应。遗传分析确定了一个母体半合子移码变体（c.1024del，p.Q341Rfs*30)在先证者中的ELF4基因。新变体通过NMD途径降低了ELF4的mRNA水平。机械上,ELF4的表达不足扰乱了免疫系统，导致免疫疾病和病原体易感性，和破坏ELF4激活IFN-β应答。该分析详细介绍了一名携带新型ELF4移码变体的中国DEX患者的临床特征。第一次,我们使用患者来源的细胞并进行转录组学分析,以深入研究DEX中ELF4变异的机制.
