Genetic testing reveals diverse pathogenic mechanisms in patients with HLH. (A) Summary of workflow for 48 subjects who underwent research-based WES analyses. (B) Genetic profiles for 101 subjects who met the HLH-2004 criteria and received genetic testing. (C) Dominant NLRC4 and NLRP12 variants and recessive NLRP4, NLRC3, and NLRP13 variants are significantly associated with development of HLH. The number of alleles containing potential protein-altering variants (frameshift insertions/deletions, stop gain/stop loss, splicing defects, nonframeshift insertions/deletions, and missense variants) in NLRC4, NLRP12, NLRP4, NLRP13, and NLRC3 in HLH-affected cases (n = 48) was compared with the number in other samples in the Baylor-Hopkins Center for Mendelian Genomics database (total n = 6677; analyzed n = 5981), which contains exomes from well-phenotyped diseased and healthy individuals (recorded within the PhenoDB database) collected among more than 380 phenotypic cohorts. Unaffected relatives in the HLH cohort (n = 51) and individuals in the Immunodeficiency cohort (n = 645) were excluded from the analysis. Differences in allelic counts between HLH cases and controls (n = 5981) were tested by random sampling without replacement (100 000 iterations).