Clonal hematopoiesis in LGI1-antibody encephalitis

Abstract

Objective: Leucine-rich glioma-inactivated 1 (LGI1)-antibody encephalitis (LGI1e), the major form of autoimmune encephalitis (AE) presented with memory loss and faciobrachial dystonic seizure, commonly develops in aged population. Hematologic aging is often accompanied by clonal hematopoiesis (CH), a phenomenon in which specific mutations accumulate, potentially leading to autoimmune disorders or malignancies. Our research aimed to investigate the connection between clonal hematopoiesis of indeterminate potential (CHIP) and LGI1e.

Methods: Peripheral blood samples from consecutive LGI1e patients were collected and analyzed for 24 clonal CHIP using targeted gene sequencing. The results were compared to a control dataset from an ethnically matched health care cohort. Patient characteristics were analyzed based on their CHIP status.

Results: A total of 52 LGI1e patients were enrolled for this study. Among them, three patients (5.8%) exhibited functional mutations in the ASXL1 gene, one of the CHIP-associated genes analyzed by targeted sequencing. This frequency was significantly higher compared to that of the control cohort (1%, p = 0.015). Nevertheless, the patients showed no difference in the clinical characteristics, laboratory results, and immunotherapy outcomes.

Interpretation: LGI1e showed high frequency of ASXL1 functional mutation in the CHIP analysis, which may contribute to the underlying pathogenesis. Further research is needed to determine its direct role in the development of autoimmunity and disease progression.

Figure 1

Oncoplot of observed clonal hematopoiesis of indeterminate potential (CHIP) mutations in leucine‐rich glioma‐inactivated 1 (LGI1)‐antibody encephalitis (LGI1e) patients. Between 2012 and 2023, we recruited 52 LGI1e patients and their DNA were collected from blood. These samples were analyzed for 24 CHIP mutant. Among these patients, only a number of patients displayed observable mutation with variant allele frequency (VAF) of ≥2. Patient number without observable mutation in sample was excluded from graph. Only three types of mutation were observable among these patients: non‐synonymous coding, frameshift, and nonsense mutation.