Whole-exome sequencing reveals the genetic landscape and polygenic susceptibility in 1241 patients with clinically suspected hemophagocytic lymphohistiocytosis

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a severe immunological disorder characterized by dysregulated immune activation. Pathogenic variants in HLH-causative genes serve as diagnostic criteria and guide treatment decisions. However, known genes do not fully explain the molecular basis of many cases, and the polygenic contribution to HLH susceptibility remains poorly characterized. Here, we retrospectively analyzed whole-exome sequencing data from 1241 patients with clinically diagnosed or suspected HLH to characterize the HLH genetic landscape. Rare variant association analysis identified two candidate susceptibility genes, IKBKG and DDX3X . Functional experiments showed that IKBKG knockdown impaired NK cell cytotoxicity and degranulation, supporting a contributory role of IKBKG in HLH-related immune dysfunction. Exploratory common variant analysis identified potential susceptibility loci, and an integrated model incorporating rare variant burden and polygenic risk score achieved an AUC of 0.71 in this cohort. These findings expand understanding of HLH genetic architecture and support contributions from both rare and common variants.