Identification of Host Genetic Factors That Are Determinant for the Development of Severe Forms of COVID-19

We conducted whole exome sequencing (WXS) on 21 cases of Multisystem Inflammatory Syndrome in Children (MIS-C) related to COVID-19 from Brazil. All patients who were hospitalized underwent serum (ELISA) and molecular (RT-PCR) testing for SARS-CoV-2, and the main clinical symptoms associated with SARS-CoV-2 infection were collected. During hospitalization, data on complications, medical interventions, and laboratory findings were also collected. Our results revealed in an unprecedented way the occurrence of several rare loss-of-function variants in the NLRP12 gene among the affected children, and three other SNVs, predicted to be highly pathogenic, were identified in the IL17RC gene. An additional nonsense variant, in the IFNA10 gene, was identified in a single patient. Through in vitro functional analysis, we unequivocally demonstrated that these mutations impact NF-kB activation. These findings are similar to those observed in NLRP12-associated systemic autoinflammatory disorders, characterized by altered innate immune response, with increased NF-κB activation and excessive production of inflammatory cytokines. To our knowledge, our study is the first to provide a plausible molecular mechanism for MIS-C involving inborn errors in NLRP12. We suggest that some patients with MIS-C may benefit from Interleukin (IL)-1 pathway blockade treatments.]]>
Inclusion Criteria for the MIS-C cases were adopted from the Centers for Disease Control and Prevention of the United States of America (CDC, 2020), which include: age under 21 yearsfever greater than or equal to 38°C for at least 24 hoursat least one laboratory evidence of inflammation [elevated C-reactive protein (CRP), d-dimer, ferritin, lactic acid dehydrogenase (LDH), elevated neutrophils, reduced lymphocytes and/or low albumin]evidence of clinically severe illness requiring hospitalization, with involvement of at least two organs (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic or neurological)positivity for SARS-CoV-2 infection by RT-PCR or serologyno alternative plausible diagnosesExclusion CriteriaIndividuals previously vaccinated against COVID-19Presence of comorbidities, including, among others, overweight, obesity, cancer, diabetes, hypertension, HIV/AIDS, asthma, tuberculosis or other systemic diseases]]>