Individuals with germline homogeneous mutations in genes essential for lymphocyte cytotoxicity, including PRF1, UNC13D, STX11, and STXBP2, typically present with familial hemophagocytic lymphohistiocytosis (FHL), a life-threatening immune dysregulation disorder characterized by marked hyperinflammation from uncontrolled activation of T-cells and macrophages. Here, PRF1 is linked to hereditary hemophagocytic lymphohistiocytosis.