Spectrum of Primary Hemophagocytic Lymphohistiocytosis-Associated Gene Mutations in Chinese Patients

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease characterized by hyperinflammation. Primary HLH (primary HLH), resulting from genetic mutations, is a subtype of HLH. The mutation spectrum of primary HLH-associated genes has not been well determined in China. This study aimed to explore the mutation spectrum of 12 primary HLH-associated genes in a multicenter database. Medical records and gene sequencing data of 1224 HLH patients were retrieved from January 2014 to September 2024, and gene mutations were analyzed. Genetic variants were observed in 350 (28.59%) patients. Among them, 108 patients had a definitive genetic diagnosis, 227 patients carried single heterozygous variants, and 15 patients carried digenic/polygenic heterozygous variants. A total of 275 different variants were identified, and missense variants were most common. Variants in UNC13D were most common, followed by LYST and PRF1, while variants in MAGT1, ITK, and CD27 were rare. For UNC13D, LYST, and PRF1, variants c.2588G>A (p.Gly863Asp), c.368A>G (p.His123Arg), and c.1349C>T (p.Thr450Met) were most common, respectively. We described the mutation spectrum of primary HLH-associated genes in a largest Chinese cohort and found some mutation specificity for Chinese HLH patients. Our data might help design sequencing panels, interpret sequencing results, and understand genetic background of Chinese HLH patients.