Retrospective Cohort Study
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Pediatr. Jun 9, 2023; 12(3): 107-114
Published online Jun 9, 2023. doi: 10.5409/wjcp.v12.i3.107
IFIH1 and DDX58 gene variants in pediatric rheumatic diseases
Rinat Raupov, Evgeny Suspitsin, Konstantin Belozerov, Tatiana Gabrusskaya, Mikhail Kostik
Rinat Raupov, Konstantin Belozerov, Mikhail Kostik, Department of Pediatry, Saint-Petersburg State Pediatric Medical University, Saint-Petersburg 194100, Russia
Evgeny Suspitsin, Department of Genetics, Saint-Petersburg State Pediatric Medical University, Saint-Petersburg 194100, Russia
Tatiana Gabrusskaya, Department of Gastrointestinal Diseases, Saint-Petersburg State Pediatric Medical University, Saint-Petersburg 194100, Russia
Author contributions: All authors contributed to the manuscript revision, read, and approved the submitted version.
Institutional review board statement: The Ethic Committee of Saint-Petersburg Sate Pediatric Medical University approved the study (protocol # 1/3 от 11.01.2021).
Informed consent statement: Written consent of legal representatives for inclusion of the data and using of the pictures was obtained.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.
STROBE statement: The authors have read the STROBE Statement-checklist of items, and the manuscript was prepared and revised according to the STROBE Statement-checklist of items.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Mikhail Kostik, MD, PhD, Professor, Department of Pediatry, Saint-Petersburg State Pediatric Medical University, Lytovskaya 2, Saint-Petersburg 194100, Russia. kost-mikhail@yandex.ru
Received: December 30, 2022
Peer-review started: December 30, 2022
First decision: January 20, 2023
Revised: February 3, 2023
Accepted: April 24, 2023
Article in press: April 24, 2023
Published online: June 9, 2023
Processing time: 159 Days and 13.9 Hours
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.