COVID-19 study with WXS data on dbGaP (21 participants)

phs003512 — Identification of Host Genetic Factors That Are Determinant for the    Development of Severe Forms of COVID-19

<p>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 <a href="https://www.ncbi.nlm.nih.gov/gene/91662">NLRP12</a> gene among the affected children, and three other SNVs, predicted to be highly pathogenic, were identified in the <a href="https://www.ncbi.nlm.nih.gov/gene/84818">IL17RC</a> gene. An additional nonsense variant, in the <a href="https://www.ncbi.nlm.nih.gov/gene/3446">IFNA10</a> gene, was identified in a single patient. Through <i>in vitro</i> functional analysis, we unequivocally demonstrated that these mutations impact NF-kB activation. These findings are similar to those observed in <a href="https://www.ncbi.nlm.nih.gov/gene/91662">NLRP12</a>-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 <a href="https://www.ncbi.nlm.nih.gov/gene/91662">NLRP12</a>. We suggest that some patients with MIS-C may benefit from Interleukin (IL)-1 pathway blockade treatments.</p>