IFIH1 and DDX58 gene variants in pediatric rheumatic diseases

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.

AIM

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.

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 DDX58 and IFI1 variants had hyperactivation of the IFN I signaling pathway.

Keywords: IFIH1, DDX58, Undifferentiated systemic autoinflammatory disease, Systemic lupus erythematosus, Interferon-I score

Core Tip: Interferon (IFN) I signaling pathway is the important part of innate immune system and antiviral defense. It’s known that defects in the components of IFN I signaling system can leads to its hyperactivation. This pathogenetic phenomenon is considered as one of the most important in the pathogenesis of immune-mediated diseases, such as systemic lupus erythematosus, dermatomyositis, systemic autoinflammatory diseases. From database containing 92 patients with different rheumatic diseases, whom clinical exome sequencing was performed we selected 14 children (10 girls and 4 boys): 7 patients had DDX58 and 7 had IFIH1 gene variants. The majority of patient with different DDX58 and IFI1 variants had hyperactivation of IFN I signaling pathway.