Introduction
The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, has resulted in an ongoing vicious pandemic. COVID-19 has a wide range of clinical outcomes ranging from no clinical symptoms to severe respiratory disease and death. Disease severity has been linked to old age and other co-morbidities. In children and infants, the infection has typically a milder and often asymptomatic course. However, Multisystem Inflammatory Syndrome in Children (MIS-C) has been recognized as a pediatric complication of severe acute respiratory syndrome coronavirus-2 infections. It is a state of hyperinflammation that typically presents 4-6 weeks after SARS-CoV-2 acute infection with high fever, organ dysfunction, and raised inflammatory markers leading to multiorgan failure and shock. Family clusters of MIS-C have been reported suggesting heritable traits predisposing to severe infection. The underlying cause of phenotypic heterogeneity, susceptibility, and disease severity among affected individuals is still unclear. It has been thought that both viral and host genetic variations could be probable factors influencing the disease severity and susceptibility. To this end, we have studied the clinical and genetic characteristics of children with MIS-C in Kuwait. Utilizing 28 large kindreds with familial MIS-C clustering, we report, here, the preliminary results obtained from three families.
Methods
Children aged ≤ 12 years who met the World Health Organization (WHO) MIS-C diagnostic criteria were identified from the national Pediatric COVID-19 Registry in Kuwait (PCR-Q8). Detailed demographic and clinical phenotype data were obtained from medical charts. All subjects and their families were invited for blood molecular genetic testing. Genetic analysis using genome sequencing at 30x depth has been performed on the affected individuals and their parents. In this abstract, we present preliminary results from three families.
Results
Sixty-seven children with MIS-C were identified in the period between April 2020 and October 2021. So far, molecular genetic testing was performed on 28 subjects and their biological parents. Genetic analysis (genome sequencing) of 3 families was completed. All of the three children were previously healthy, non-obese, with no known co-morbidities, and no family history of MIS-C. They all had evidence of recent SARS-CoV-2 infection (positive RT-PCR result and positive IgG antibody detection). One child aged 9 years developed myocarditis as a complication of MIS-C. He presented with hypotension, hemodynamic instability, and required inotropic support. All three kids have fully recovered after receiving respiratory support in the Pediatric Intensive Care Unit (PICU). Consanguinity was observed in two families. Probands harbored various homozygous variants in the BTNL8, IL17RA, and IRS4 genes will be presented and discussed.
Conclusion
This is the first study to review the demographic, clinical, epidemiological, and genetic characteristics of children with MIS-C in Kuwait. Although familial clustering of severe COVID-19 infection has not been observed in our cohort, our data shows that utilizing a family-based study allows for significant enrichment for homozygous genetic variants that may impact our understanding of MIS-C.