Schematic of novel genetic burden testing method. (A) The top part of the flowchart represents the cohort-specific analysis steps, including ancestry assignment and variant aggregation. (B) The bottom part of the flowchart represents the Monte Carlo simulations of control datasets using population-level AFs from public databases. Stringent quality control and variant filtering is performed both at the cohort and the database level. Variants that don’t pass the criteria in either dataset are automatically excluded from all downstream analyses. (C) The cohort-specific results are compared to the empirical burden distribution to estimate statistical significance. (D) PCA plot that depicts the inferred ancestry of all samples in the MIS-C burden analysis.