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Multicenter Study
. 2023 Jul 31:13:1182257.
doi: 10.3389/fcimb.2023.1182257. eCollection 2023.

Rare genetic variants involved in multisystem inflammatory syndrome in children: a multicenter Brazilian cohort study

Bárbara Carvalho Santos Dos Reis  1   2   3 , Roberta Soares Faccion  1   2 , Flavia Amendola Anisio de Carvalho  1   3 , Daniella Campelo Batalha Cox Moore  4   5 , Maria Celia Chaves Zuma  1   2 , Desirée Rodrigues Plaça  6   7 , Igor Salerno Filgueiras  8 , Dennyson Leandro Mathias Fonseca  9 , Otavio Cabral-Marques  6   8   9   10   11   12 , Adriana Cesar Bonomo  13   14   15   16 , Wilson Savino  13   14   15   16 , Flávia Cristina de Paula Freitas  17 , Helisson Faoro  17 , Fabio Passetti  17 , Jaqueline Rodrigues Robaina  18 , Felipe Rezende Caino de Oliveira  19 , Ana Paula Novaes Bellinat  20 , Raquel de Seixas Zeitel  21 , Margarida Dos Santos Salú  1   2   20 , Mariana Barros Genuíno de Oliveira  18 , Gustavo Rodrigues-Santos  18 , Arnaldo Prata-Barbosa  18   22 , Zilton Farias Meira de Vasconcelos  2
Affiliations
Multicenter Study

Rare genetic variants involved in multisystem inflammatory syndrome in children: a multicenter Brazilian cohort study

Bárbara Carvalho Santos Dos Reis et al. Front Cell Infect Microbiol. .

Abstract

Introduction: Despite the existing data on the Multisystem Inflammatory Syndrome in Children (MIS-C), the factors that determine these patients evolution remain elusive. Answers may lie, at least in part, in genetics. It is currently under investigation that MIS-C patients may have an underlying innate error of immunity (IEI), whether of monogenic, digenic, or even oligogenic origin.

Methods: To further investigate this hypothesis, 30 patients with MIS-C were submitted to whole exome sequencing.

Results: Analyses of genes associated with MIS-C, MIS-A, severe covid-19, and Kawasaki disease identified twenty-nine patients with rare potentially damaging variants (50 variants were identified in 38 different genes), including those previously described in IFNA21 and IFIH1 genes, new variants in genes previously described in MIS-C patients (KMT2D, CFB, and PRF1), and variants in genes newly associated to MIS-C such as APOL1, TNFRSF13B, and G6PD. In addition, gene ontology enrichment pointed to the involvement of thirteen major pathways, including complement system, hematopoiesis, immune system development, and type II interferon signaling, that were not yet reported in MIS-C.

Discussion: These data strongly indicate that different gene families may favor MIS- C development. Larger cohort studies with healthy controls and other omics approaches, such as proteomics and RNAseq, will be precious to better understanding the disease dynamics.

Keywords: Kawasaki disease; coronavirus infection; mucocutaneous lymph node syndrome; multisystem inflammatory syndrome in children; pediatric inflammatory multisystem syndrome; whole exome sequencing.

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Conflict of interest statement

The authors declare that this research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Functional relationships between genes with CV (candidate variants) in MISC patients. (A) Protein-Protein Interaction (PPI) Networks based on experimental evidence and expert-curated databases. Left panel: genes with CV identified in our study. Middle panel: genes with CV identified in our study plus genes with CV previously reported in literature. Right panel: genes with CV previously reported in literature. Genes that encode Complement System proteins are in orange, proteins in Response to virus pathways in green, including interferon pathway genes (yellow), and genes that regulate DNA processes in blue. IS: Immune system. Gene network analyses performed in String. Panels (B–D) depict Chord diagrams illustrating the functional relationships between the genes of (B) our study, (C) literature, and (D) our data and literature data combined and the biological processes (BP) that enrich them according to GO functional enrichment analysis. BPs are indicated by numbers. BPs enriched only by our study genes are in green, BPs enriched only by the literature genes in yellow, BPs that are enriched for both gene sets in orange, and BPs that only appear enriched with the combination of our genes with literature genes in purple. The size of the rectangles is proportional to the involvement of genes in the multiple pathways. Genes from each data set that does not enrich any BP does not appear in the images. The scale outside the circles indicates the number of relationships for each rectangle. Images created using circlize R package in R version 4.0.5. Colors for pathways, genes, and BPs are arbitrary. *Because TERC is not translated into a protein, String Nodes analysis does not include this gene. **We identified 38 genes with CV in MISC patients and other groups had previously described 41 genes. Because we identified CV in 3 genes that had already been described, accounting for those, the current total of genes with CV regarding MISC is 78 genes.
Figure 2
Figure 2
Schematic representation of the six major pathways identified by functional relationships between MISC patients’ genes with CV described by the present study. Three of these are uniquely identified when genes previously reported and genes in our study are analyzed together (Angiogenesis, Cell adhesion, and Exocytosis) and three others emerged exclusively from the analysis of the genes with CV in our patients (Complement system, Hematopoiesis and Immune system development, and Type 2 interferon signaling pathway). The inner circle depicts the pathways and the outer circle the genes with CV involved in each pathway. The size of each pathway in the inner circle is proportional to the number of patients with a respective gene with CV.
See this image and copyright information in PMC

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Supplementary concepts