Fernando G. I. Freire

Brazil

Inborn Errors in the Type I Interferon Signaling Pathway in Children with Multisystem Inflammatory Syndrome Associated with SARS-CoV-2 Infection

Fernando Freire1,2, Raquel Bispo1,3, Ryan Francisco1, Sâmek Novaes1, Pablo Oliveira1

1. Laboratory of Genomics and Complex Diseases, University Federal da Bahia, Brazil
2. Laboratory of Immunology and Molecular Biology, University Federal da Bahia, Brazil
3. Gonçalo Moniz Institute – Fiocruz, IGM – FIOCRUZ, Brazil

Abstract

Background

Pediatric Multisystem Inflammatory Syndrome (MIS-C) is a rare hyperinflammatory condition linked to prior SARS-CoV-2 infection, with a possible association with inborn errors of immunity. We conducted a study using Whole Exome Sequencing (WES) in 21 hospitalized children from Northeastern Brazil, focusing on genes in the Type I Interferon (IFN) pathway. Clinical and laboratory findings, including gastrointestinal, cardiac, and mucocutaneous involvement, were compared with international cohorts through a systematic review. Variant analysis highlighted potential alterations in Interferon-Stimulated Genes (ISGs) and identified four key genes—NLRX1, IFI35, IFI27, and GBP2—as relevant based on GTEx annotations. These results offer novel insights into genetic contributions to MIS-C.

Methods

We conducted a cross-sectional study to investigate the genetic contributions to MIS-C, collecting clinical and demographic data from three hospitals in Northeastern Brazil (May 2020 to March 2021). We performed a systematic review comparing the clinical and laboratory characteristics of MIS-C with international cohorts.
Finally, we performed whole exome sequencing (WES) of our cohort, analyzing protein-coding regions, generating 265,627 variants, with 65,286 in exons or splice sites. Variants were filtered based on pathway relevance, allele frequency (MAF ? 0.01), and harmfulness (CADD ? 15). Gene expression data from the GTEx Portal highlighted IFN-related genes, offering insights into genetic and clinical associations of MIS-C.

Results

In this study, we identified 588 articles on MIS-C from PubMed/Medline, of which 581 were excluded based on criteria, resulting in a final selection of 7 studies for review. Our cohort consisted of 21 participants, compared with 838 in the systematic review. Due to the absence of laboratory values ??in one included study, the sample size was adjusted to 754 for the analysis of clinical outcomes.
Genetic analysis revealed 10 variants in 11 genes associated with the type I interferon pathway, including GBP2, IFI27, IFI35, IFIT2, IFNA5, NLRC4, NLRP12, NLRP2, NLRX1, and NOD2. These genes showed moderate genetic intolerance, with pLI values ??of 0.69 for IFI27 and 0.31 for IFNA5. Notably, the IFI35, IFI27, and GBP2 genes exhibited multisystemic expression, particularly in adipose tissue, aorta, coronary artery, and spleen. These findings suggest that deleterious variants in these genes may play a role in the clinical manifestations of MIS-C.

Conclusions

In conclusion, the analysis of genetic variants, including pLI and CADD scores, is crucial for understanding the role of mutations in diseases like MIS-C. While elevated pLI values suggest the potential pathogenicity of mutations, further evidence is needed to validate their functional impact. Additionally, the late onset of MIS-C may be influenced by environmental factors and the accumulation of pathogenic variants. The cross-sectional nature of the analysis presents limitations, such as incomplete demographic data and variability in laboratory values across studies. Despite these challenges, genetic associations and expression profiles of interferon-stimulated genes may offer valuable insights into MIS-C pathogenesis and serve as potential biomarkers for future infections. Further research is necessary to elucidate these mechanisms.