Whole-genome sequencing reveals genetic backgrounds in Japanese patients with hemophagocytic lymphohistiocytosis treated with the HLH-2004 protocol

Background: Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory condition triggered by a combination of genetic predispositions and environmental factors. Reports of previous outcomes from the HLH-2004 protocol in Japan revealed patients with idiopathic HLH who had poor prognoses. This study aimed to reevaluate the genetic background of such patients to identify potential novel genetic variants. Methods: Whole-genome sequencing was performed on residual samples from HLH patients enrolled in a study of the HLH-2004 protocol in Japan, excluding those associated with Epstein–Barr virus infection. Sequence variants were interpreted based on the American College of Medical Genetics and Genomics standards and guidelines. Results: Nineteen patients were analyzed, including seven diagnosed with familial HLH (FHL) and twelve with unknown causes. Among patients with FHL, five had variants in PRF1 and two in UNC13D, consistent with the original diagnoses. Genetic variants (all UNC13D) were identified in three of the 12 previously undiagnosed patients. One patient had an unknown outcome and the others died of HLH. Conclusion: Failure to establish a genetic diagnosis during initial evaluation may have negatively impacted the prognosis of patients with HLH. Comprehensive genetic studies and the development of early screening methods may improve treatment outcomes for HLH.