Autoinflammatory Diseases and Immunodeficiencies Centre, Pediatric Rheumatology Clinic, IRCCS Giannina Gaslini Institute, University of Genoa.
Medical Genetics Unit, IRCCS Giannina Gaslini Institute.
Rheumatology (Oxford). 2020 Feb 1;59(2):344-360. doi: 10.1093/rheumatology/kez270.
The number of innate immune system disorders classified as systemic autoinflammatory diseases (SAID) has increased in recent years. More than 70% of patients with clinical manifestations of SAID did not receive a molecular diagnosis, thus being classed as so-called undifferentiated or undefined SAID (uSAID). The aim of the present study was to evaluate a next-generation sequencing (NGS)-based clinically oriented protocol in patients with uSAID.
We designed a NGS panel that included 41 genes clustered in seven subpanels. Patients with uSAID were classified into different groups according to their clinical features and sequenced for the coding portions of the 41 genes.
Fifty patients were enrolled in the study. Thirty-four patients (72%) displayed recurrent fevers not consistent with a PFAPA phenotype. Sixteen patients displayed a chronic inflammatory disease course. A total of 100 gene variants were found (mean 2 per patient; range 0-6), a quarter of which affected suspected genes. Mutations with a definitive diagnostic impact were detected in two patients. Patients with genetically negative recurrent fevers displayed a prevalent gastrointestinal, skin and articular involvement. Patients responded to steroids on demands (94%) and colchicine, with a response rate of 78%.
Even with a low molecular diagnostic rate, a NGS-based approach is able to provide a final diagnosis in a proportion of uSAID patients with evident cost-effectiveness. It also allows the identification of a subgroup of genetically negative patients with recurrent fever responding to steroid on demand and colchicine.
近年来，被归类为系统性自身炎症性疾病（SAID）的先天免疫系统疾病数量有所增加。超过 70%的具有 SAID 临床表现的患者未接受分子诊断，因此被归类为所谓的未分化或未定义的 SAID（uSAID）。本研究旨在评估一种基于下一代测序（NGS）的临床定向方案在 uSAID 患者中的应用。
我们设计了一个 NGS 面板，其中包含 41 个基因，分为七个子面板。根据患者的临床特征，将 uSAID 患者分为不同组，并对 41 个基因的编码部分进行测序。
共有 50 名患者入组研究。34 名患者（72%）出现反复发作的发热，与 PFAPA 表型不一致。16 名患者表现为慢性炎症性疾病过程。共发现 100 种基因变异（平均每位患者 2 种；范围 0-6），其中四分之一影响疑似基因。在两名患者中发现了具有明确诊断意义的突变。具有遗传阴性复发性发热的患者表现出普遍的胃肠道、皮肤和关节受累。94%的患者对类固醇有反应，78%的患者对秋水仙碱有反应。
即使分子诊断率较低，基于 NGS 的方法也能够为具有明显成本效益的一部分 uSAID 患者提供最终诊断。它还可以确定一组具有遗传阴性复发性发热且对需求性类固醇和秋水仙碱有反应的患者。
