and gene variants in pediatric rheumatic diseases.

Background: The gene codes the MDA5 protein and the 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.

Aim: To characterize children with pediatric rheumatic diseases (PRD) carrying or variants.

Methods: Clinical exome sequencing was performed on 92 children with different PRD. and 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) ( = 2), myelodysplastic syndrome with SLE features at the onset of the disease ( = 1), mixed connective tissue disease (MCTD) ( = 1), undifferentiated systemic autoinflammatory disease (uSAID) ( = 3) have 5 different variants of the 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 variants. Seven patients had six different variants. They were presented with uSAID ( = 2), juvenile dermatomyositis (JDM) ( = 1), SLE-like disease ( = 1), Periodic fever with aphthous stomatitis, pharyngitis, and adenitis syndrome ( = 1), and systemic onset juvenile idiopathic arthritis ( = 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.

Conclusion: 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 and variants had hyperactivation of the IFN I signaling pathway.