X-linked hyper IgM syndrome with a novel CD40-ligand gene mutation suffered from infection of Talaromyces marneffei.

Authors

Juan Gu, Aiyan Ren, Jing Kong, Meiying Huang, Huijuan Jin, Chengxin Sun, Shiji Xiao, Enming Zhang, Zuochen Du

Published in

Frontiers in immunology. Volume 17. Pages 1875082. Epub Sep 29, 2026.

Abstract

X-linked Hyper-IgM Syndrome (X-HIGM) is a primary immunodeficiency caused by pathogenic variants in CD40L. Loss of functional CD40 ligand interferes with T-cell-dependent B-cell responses and immunoglobulin class-switch recombination, resulting in susceptibility to recurrent and opportunistic infections. Because CD40L is located on the X chromosome, X-HIGM is usually diagnosed in males. Symptomatic females are rare, and the clinical and immunological features of these patients have not been well defined.
We report a 4-year-old Chinese girl who developed disseminated Talaromyces marneffei infection and was subsequently diagnosed with X-HIGM. Her clinical history and laboratory findings were reviewed, and a comprehensive immunological evaluation was performed, including flow cytometric analysis. Genetic testing was carried out by next-generation sequencing, and the identified variant was confirmed by Sanger sequencing. The possible effect of the CD40L c.364 + 2T>A variant on RNA splicing was examined using the online AI tool RNA-Splicer. We also analyzed peripheral blood mononuclear cells (PBMCs) from the patient and an age- and sex-matched healthy control by single-cell RNA sequencing to further characterize abnormalities in peripheral immune-cell populations and their transcriptional profiles.
A previously undescribed heterozygous CD40L c.364 + 2T>A variant was identified in the patient and was confirmed to be de novo. Analysis of the PBMC transcriptomes showed differences across several immune-cell compartments. In particular, B-cell populations showed impaired programs related to maturation and immunoglobulin class switching, while alterations were also observed in T-cell developmental states. The proportions of several myeloid and dendritic-cell populations were reduced in the patient. In addition, cell-cell communication analysis indicated changes in interactions among multiple immune-cell subsets.
We identified a de novo splice-site variant in CD40LG in a symptomatic female child with X-HIGM and disseminated T. marneffei infection. The clinical presentation and single-cell transcriptomic findings highlight the broad effects of CD40L deficiency on the peripheral immune system. This case adds a previously unreported CD40LG variant to the spectrum of genetic changes associated with X-HIGM and provides additional information on the immune abnormalities that may occur in symptomatic female patients.

PMID:
42871086
Bibliographic data and abstract were imported from PubMed on 14 Oct 2026.

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