Unlike familial HLH, where mutations lead to defects in transport, exocytosis, or the content of cytotoxic granules in T and NK cells, the disease described here is due to homozygous mutations in Nck-associated protein 1–like (NCKAP1L), a key component of the actin cytoskeleton machinery. Here, NCKAP1L is linked to hemophagocytic syndrome.