A novel CD40LG frameshift mutation in an Iranian family with X-linked hyper-IgM syndrome: A case report

Pathogenic mutations in the CD40LG gene lead to X-linked hyper-IgM syndrome type 1 (X-HIGM1), a rare primary immunodeficiency marked by impaired class-switch recombination of immunoglobulins and frequent severe infections. Early molecular diagnosis is essential for appropriate management, genetic counseling, and prenatal diagnosis.

We investigated a 5-year-old Iranian boy with recurrent otitis media and pneumonia since infancy, progressive inflammatory arthritis, and a striking family history of early male deaths suggestive of an inherited X-linked immunodeficiency. Baseline immunological evaluation before initiation of IVIG showed markedly reduced IgG (2 mg/dL) and undetectable IgA (0 mg/dL), while IgM remained within the reference range (114 mg/dL). Lymphocyte subset analysis showed no major abnormality in the distribution of conventional T-cell subsets. Whole-exome sequencing (WES) revealed a hemizygous frameshift mutation in CD40LG, c.127del (p.Ala43LeufsTer11), predicted to introduce a premature termination codon and result in loss of normal CD40LG function. Sanger sequencing confirmed the variant in the proband and identified his mother as a heterozygous carrier, with the segregation pattern in the tested family members consistent with X-linked inheritance. Prenatal testing further showed that the fetus did not carry the pathogenic variant.

According to ACMG/AMP criteria, the c.127del variant was classified as pathogenic based on predicted loss of function, absence from population databases, phenotype specificity, and segregation evidence (PVS1, PM2_supporting, PP1_supporting, PP4). This variant affects exon 1 of CD40LG, a less commonly reported region compared with the known mutational hotspot in exon 5.

We report a novel pathogenic CD40LG frameshift variant associated with X-HIGM1 in an Iranian family. This report broadens the CD40LG mutation spectrum and underscores the utility of WES for confirming diagnosis, identifying carriers, enabling genetic counseling, and directing prenatal diagnosis for families with suspected X-linked immunodeficiency.