PDF(Pubmed)
Abstract：
BACKGROUND: The IFIH1 gene codes the MDA5 protein and the DDX58 gene codes the RIG-I receptor. Both proteins are parts of the interferon (IFN) I signaling pathway and are responsible for antiviral defense and innate immune response. IFIH1 and DDX58 polymorphisms are associated with a spectrum of autoimmune diseases. Rare gain-of-function IFIH1 mutations have been found in Singleton-Merten and Aicardi-Goutières syndrome, while DDX58 mutation can cause atypical Singleton-Merten syndrome.
OBJECTIVE: To characterize children with pediatric rheumatic diseases (PRD) carrying DDX58 or IFIH1 variants.
METHODS: Clinical exome sequencing was performed on 92 children with different PRD. IFIH1 and DDX58 variants have been detected in 14 children. IFN-I score has been analyzed and the clinical characteristics of patients have been studied.
RESULTS: A total of seven patients with systemic lupus erythematosus (SLE) (n = 2), myelodysplastic syndrome with SLE features at the onset of the disease (n = 1), mixed connective tissue disease (MCTD) (n = 1), undifferentiated systemic autoinflammatory disease (uSAID) (n = 3) have 5 different variants of the DDX58 gene. A common non-pathogenic variant p.D580E has been found in five children. A rare variant of uncertain significance (VUS) p.N354S was found in one patient with uSAID, a rare likely non-pathogenic variant p.E37K in one patient with uSAID, and a rare likely pathogenic variant p.Cys864fs in a patient with SLE. Elevated IFN-I score was detected in 6 of 7 patients with DDX58 variants. Seven patients had six different IFIH1 variants. They were presented with uSAID (n = 2), juvenile dermatomyositis (JDM) (n = 1), SLE-like disease (n = 1), Periodic fever with aphthous stomatitis, pharyngitis, and adenitis syndrome (n = 1), and systemic onset juvenile idiopathic arthritis (n = 1). Three patients have VUS p.E627X, one patient has benign variant p.I923V. Rare VUS p.R595H was detected in the JDM patient. Another rare VUS p.L679Ifs*2 and previously not reported variant p.V599Ffs*5 were detected in the patient with uSAID. One patient with uSAID has rare VUS p.T520A. All patients had elevated IFN-I scores.
CONCLUSIONS: Rare compound-heterozygous IFIH1 variant (p.L679Ifs*2 and p.V599Ffs*5), heterozygous IFIH1 variant (p.T520A) and heterozygous DDX58 variant (p.Cys864fs) are probably disease causative for uSAID and SLE. The majority of patients with different DDX58 and IFI1 variants had hyperactivation of the IFN I signaling pathway.
OBJECTIVE: To characterize children with pediatric rheumatic diseases (PRD) carrying DDX58 or IFIH1 variants.
METHODS: Clinical exome sequencing was performed on 92 children with different PRD. IFIH1 and DDX58 variants have been detected in 14 children. IFN-I score has been analyzed and the clinical characteristics of patients have been studied.
RESULTS: A total of seven patients with systemic lupus erythematosus (SLE) (n = 2), myelodysplastic syndrome with SLE features at the onset of the disease (n = 1), mixed connective tissue disease (MCTD) (n = 1), undifferentiated systemic autoinflammatory disease (uSAID) (n = 3) have 5 different variants of the DDX58 gene. A common non-pathogenic variant p.D580E has been found in five children. A rare variant of uncertain significance (VUS) p.N354S was found in one patient with uSAID, a rare likely non-pathogenic variant p.E37K in one patient with uSAID, and a rare likely pathogenic variant p.Cys864fs in a patient with SLE. Elevated IFN-I score was detected in 6 of 7 patients with DDX58 variants. Seven patients had six different IFIH1 variants. They were presented with uSAID (n = 2), juvenile dermatomyositis (JDM) (n = 1), SLE-like disease (n = 1), Periodic fever with aphthous stomatitis, pharyngitis, and adenitis syndrome (n = 1), and systemic onset juvenile idiopathic arthritis (n = 1). Three patients have VUS p.E627X, one patient has benign variant p.I923V. Rare VUS p.R595H was detected in the JDM patient. Another rare VUS p.L679Ifs*2 and previously not reported variant p.V599Ffs*5 were detected in the patient with uSAID. One patient with uSAID has rare VUS p.T520A. All patients had elevated IFN-I scores.
CONCLUSIONS: Rare compound-heterozygous IFIH1 variant (p.L679Ifs*2 and p.V599Ffs*5), heterozygous IFIH1 variant (p.T520A) and heterozygous DDX58 variant (p.Cys864fs) are probably disease causative for uSAID and SLE. The majority of patients with different DDX58 and IFI1 variants had hyperactivation of the IFN I signaling pathway.
摘要：
背景：IFIH1基因编码MDA5蛋白，DDX58基因编码RIG-I受体。两种蛋白质都是干扰素（IFN）I信号通路的一部分，负责抗病毒防御和先天免疫反应。IFIH1和DDX58多态性与一系列自身免疫性疾病有关。在Singleton-Merten和Aicardi-Goutières综合征中发现了罕见的功能获得IFIH1突变，而DDX58突变可引起非典型Singleton-Merten综合征。
目的：研究儿童风湿性疾病（PRD）携带DDX58或IFIH1变异的特征。
方法：对92例不同PRD患儿进行临床外显子组测序。在14名儿童中检测到IFIH1和DDX58变体。已经分析了IFN-I评分并研究了患者的临床特征。
结果：共有7例系统性红斑狼疮（SLE）患者（n=2），在疾病发作时具有SLE特征的骨髓增生异常综合征（n=1），混合性结缔组织病（MCTD）（n=1），未分化的全身性自身炎性疾病(uSAID)(n=3)具有5种不同的DDX58基因变体。在五个儿童中发现了一种常见的非致病性变异p.D580E。在一名uSAID患者中发现了一种罕见的不确定意义（VUS）p.N354S变异，在一名uSAID患者中，一种罕见的可能的非致病性变异p.E37K，和SLE患者中罕见的可能致病变异p.Cys864fs。在7名DDX58变体患者中的6名检测到IFN-I评分升高。7名患者有6种不同的IFIH1变异。他们出现了uSAID（n=2），青少年皮肌炎（JDM）（n=1），SLE样疾病（n=1），周期性发热伴口疮性口炎，咽炎,和结肠炎综合征（n=1），和全身发作的幼年特发性关节炎（n=1）。三名患者有VUSp.E627X，一名患者患有良性变异p.I923V。在JDM患者中检测到罕见的VUSp.R595H。在uSAID患者中检测到另一个罕见的VUSp.L679Ifs*2和以前未报道的变异p.V599Ffs*5。一名uSAID患者患有罕见的VUSp.T520A。所有患者的IFN-I评分均升高。
结论：稀有复合杂合IFIH1变体（p。L679Ifs*2和p.V599Ffs*5)，杂合IFIH1变体（p。T520A）和杂合DDX58变体（p。Cys864fs)可能是uSAID和SLE的致病原因。大多数具有不同DDX58和IFI1变体的患者具有IFNI信号通路的过度激活。
目的：研究儿童风湿性疾病（PRD）携带DDX58或IFIH1变异的特征。
方法：对92例不同PRD患儿进行临床外显子组测序。在14名儿童中检测到IFIH1和DDX58变体。已经分析了IFN-I评分并研究了患者的临床特征。
结果：共有7例系统性红斑狼疮（SLE）患者（n=2），在疾病发作时具有SLE特征的骨髓增生异常综合征（n=1），混合性结缔组织病（MCTD）（n=1），未分化的全身性自身炎性疾病(uSAID)(n=3)具有5种不同的DDX58基因变体。在五个儿童中发现了一种常见的非致病性变异p.D580E。在一名uSAID患者中发现了一种罕见的不确定意义（VUS）p.N354S变异，在一名uSAID患者中，一种罕见的可能的非致病性变异p.E37K，和SLE患者中罕见的可能致病变异p.Cys864fs。在7名DDX58变体患者中的6名检测到IFN-I评分升高。7名患者有6种不同的IFIH1变异。他们出现了uSAID（n=2），青少年皮肌炎（JDM）（n=1），SLE样疾病（n=1），周期性发热伴口疮性口炎，咽炎,和结肠炎综合征（n=1），和全身发作的幼年特发性关节炎（n=1）。三名患者有VUSp.E627X，一名患者患有良性变异p.I923V。在JDM患者中检测到罕见的VUSp.R595H。在uSAID患者中检测到另一个罕见的VUSp.L679Ifs*2和以前未报道的变异p.V599Ffs*5。一名uSAID患者患有罕见的VUSp.T520A。所有患者的IFN-I评分均升高。
结论：稀有复合杂合IFIH1变体（p。L679Ifs*2和p.V599Ffs*5)，杂合IFIH1变体（p。T520A）和杂合DDX58变体（p。Cys864fs)可能是uSAID和SLE的致病原因。大多数具有不同DDX58和IFI1变体的患者具有IFNI信号通路的过度激活。
