When applied to a heterogeneous cohort of 58 patients, with a clinical diagnosis of HLH (n = 56) or with a functional defect suggestive of primary HLH (n = 2; defective NK cell activity combined with defective exocytosis or decreased perforin expression), we identified 22 disease-causing mutations, of which eight were novel, in six of the twelve genes included in the panel. This evidence concerns the gene PRF1 and hemophagocytic syndrome.