Lili Gao and colleagues present a whole-exome sequencing analysis to search the potential “second-hit” mechanism that underlies the onset of Familial hemophagocytic lymphohistiocytosis type 2(FHL2). They have found a novel type of compound heterozygous mutation in PRF1 and a homozygous germline mutation in PCDH18. Their findings strongly argue that the presence of a “second” germline mutation besides the PRF1 gene might be potentially an important mechanism for triggering the onset of FHL2.