HLH-associated genes and digenic inheritance. A simplified pathway of formation, polarization, and transport of cytotoxic granules that is essential for lymphocyte cytotoxicity is shown. Biallelic mutations have been reported for all of these genes in patients with fHLH. Zhang et al¹  describe digenic heterozygous mutations in the highlighted genes. Digenic mutations in degranulation pathway genes (blue/blue) in this series had earlier onset of disease than digenic mutations in a degranulation pathway gene and PRF1 (blue/red).