Host genetic susceptibility underlying SARS-CoV-2-associated Multisystem Inflammatory Syndrome in Brazilian Children

Multisystem Inflammatory Syndrome in Children (MIS-C) is a life-threatening complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which manifests as a hyper inflammatory process with multiorgan involvement in predominantly healthy children in the weeks following mil...

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Published in:	Molecular medicine (Cambridge, Mass.) Vol. 28; no. 1; pp. 153 - 13
Main Authors:	Santos-Rebouças, Cíntia Barros, Piergiorge, Rafael Mina, Dos Santos Ferreira, Cristina, Seixas Zeitel, Raquel de, Gerber, Alexandra Lehmkuhl, Rodrigues, Marta Cristine Felix, Guimarães, Ana Paula de Campos, Silva, Rodrigo Moulin, Fonseca, Adriana Rodrigues, Souza, Rangel Celso, de Souza, Ana Tereza Antunes Monteiro, Rossi, Átila Duque, Porto, Luís Cristóvão de Moraes Sobrino, Cardoso, Cynthia Chester, de Vasconcelos, Ana Tereza Ribeiro
Format:	Journal Article
Language:	English
Published:	England BioMed Central 12-12-2022 BMC
Subjects:	Admixed population ATP-Binding Cassette Transporters Child COVID-19 COVID-19 - complications COVID-19 - genetics Disease prevention Genes Genetic Predisposition to Disease Genetic testing Genomes Host genetics Humans Infections Kawasaki disease Multisystem Inflammatory Syndrome in Children Mutation Neutrophils Pediatrics SARS-CoV-2 Serology Severe acute respiratory syndrome coronavirus 2 Systemic Inflammatory Response Syndrome - genetics T cell receptors Admixed population COVID-19 complications Host genetics SARS-CoV-2 Multisystem Inflammatory Syndrome in Children
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Summary:	Multisystem Inflammatory Syndrome in Children (MIS-C) is a life-threatening complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which manifests as a hyper inflammatory process with multiorgan involvement in predominantly healthy children in the weeks following mild or asymptomatic coronavirus disease 2019 (COVID-19). However, host monogenic predisposing factors to MIS-C remain elusive. Herein, we used whole exome sequencing (WES) on 16 MIS-C Brazilian patients to identify single nucleotide/InDels variants as predisposition factors associated with MIS-C. We identified ten very rare variants in eight genes (FREM1, MPO, POLG, C6, C9, ABCA4, ABCC6, and BSCL2) as the most promising candidates to be related to a higher risk of MIS-C development. These variants may propitiate a less effective immune response to infection or trigger the inflammatory response or yet a delayed hyperimmune response to SARS-CoV-2. Protein-Protein Interactions (PPIs) among the products of the mutated genes revealed an integrated network, enriched for immune and inflammatory response mechanisms with some of the direct partners representing gene products previously associated with MIS-C and Kawasaki disease (KD). In addition, the PPIs direct partners are also enriched for COVID-19-related gene sets. HLA alleles prediction from WES data allowed the identification of at least one risk allele in 100% of the MIS-C patients. This study is the first to explore host MIS-C-associated variants in a Latin American admixed population. Besides expanding the spectrum of MIS-C-associated variants, our findings highlight the relevance of using WES for characterising the genetic interindividual variability associated with COVID-19 complications and ratify the presence of overlapping/convergent mechanisms among MIS-C, KD and COVID-19, crucial for future therapeutic management.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1076-1551 1528-3658 1528-3658
DOI:	10.1186/s10020-022-00583-5