Identification of germline variants in adults with hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder of immune system overactivation that occurs as familial and acquired forms.1 HLH is characterized by excessive cytokine production and inflammation, mediated by multiple immune cells including persistently activated macrophages. Familial HLH (FHL) is typically diagnosed in childhood and is often caused by inherited biallelic, deletion, or truncating variants in genes regulating the cytotoxic function of T lymphocytes and natural killer cells.2,3 By contrast, acquired HLH usually occurs in the setting of malignancy, infection, or autoimmune disease, and may be diagnosed at any age. Prior studies using in silico prediction algorithms have concluded that germline HLH-associated variants are enriched in adult patients with HLH but have been limited in the number of genes analyzed, incomplete clinical annotation to confirm true HLH diagnoses, and the relatively small size of the adult cohorts. Finally, the comparatively young ages at the time of HLH onset have made distinguishing FHL that occurs in early adulthood from true adult-onset HLH difficult.4-6 To overcome these issues, we sought to identify potential pathogenic germline variants in 17 genes implicated in FHL or other inherited immune disorders in a highly annotated cohort of patients diagnosed with HLH in adulthood.7