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

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.