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

Autor: Cíntia Barros Santos-Rebouças, Rafael Mina Piergiorge, Cristina dos Santos Ferreira, Raquel de Seixas Zeitel, Alexandra Lehmkuhl Gerber, Marta Cristine Felix Rodrigues, Ana Paula de Campos Guimarães, Rodrigo Moulin Silva, Adriana Rodrigues Fonseca, Rangel Celso Souza, Ana Tereza Antunes Monteiro de Souza, Átila Duque Rossi, Luís Cristóvão de Moraes Sobrino Porto, Cynthia Chester Cardoso, Ana Tereza Ribeiro de Vasconcelos
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Zdroj: Molecular Medicine, Vol 28, Iss 1, Pp 1-13 (2022)
Druh dokumentu: article
ISSN: 1076-1551
1528-3658
DOI: 10.1186/s10020-022-00583-5
Popis: Abstract Background 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. Methods 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. Results 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. Conclusions 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.
Databáze: Directory of Open Access Journals
Externí odkaz: