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

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.

High Fatality Rates in Pediatric Multisystem Inflammatory Syndrome: A Multicenter Experience From the Epicenter of Brazil’s Coronavirus Pandemic

“…Host genetic variants and monogenic causes are being evaluated as predisposing factors for MIS-C, 30 including in the Brazilian population. 31 While underdiagnosis could partially explain the high lethality in our study, we believe in the study group’s high sensibility for detecting MIS-C cases: disease awareness has been historically high in teaching hospitals (responsible for more than 80% of the participating sites), and virtually all the study’s authors were directly involved with care in the emergency and PICU. A multicenter, prospective cohort study conducted in 17 private and public PICUs in 5 Brazilian provinces reported 56 patients with MIS-C, with only 1 death (CFR = 1.8%).…”

The plasma proteome differentiates the multisystem inflammatory syndrome in children (MIS-C) from children with SARS-CoV-2 negative sepsis

“…Upregulated PRDX6 in the MIS-C cohort may regulate lung phospholipid metabolism, lipid peroxidation repair, and inflammatory signaling [ 112 ]. MPO, a neutrophil lysosomal protein that regulates the formation of reactive oxygen species [ 113 ], was increased in MIS-C. Variants in the MPO gene have been associated with greater MIS-C susceptibility [ 114 – 116 ]. Lastly, C3, CXCL11, and CCL5 are established immune proteins that were elevated in our MIS-C cohort and have been previously identified to be elevated in COVID-19 patients [ 117 – 119 ].…”

Multisystem Inflammatory Syndrome in Children and Kawasaki Disease: Parallels in Pathogenesis and Treatment

“…Outside of the observation that MIS-C typically develops 2–6 weeks after infection with COVID-19, other underlying risk factors remain largely unknown. Gene sequencing in small MIS-C cohorts has identified potential genetic variants affecting the inflammasome, interferon signaling, the complement system, and adaptive immunity, but these findings need to be validated in larger cohorts [ 14 , 15 ]. For some individuals, MIS-C may indicate an underlying disorder of immune dysregulation due to a genetic risk factor that is incompletely penetrant.…”