CD40LG – X-linked Hyper-IgM Syndrome

X-linked Hyper-IgM (HIGM1) syndrome is caused by hemizygous loss-of-function mutations in CD40LG, encoding the T-cell ligand for CD40. CD40L deficiency abolishes T-cell–dependent B-cell class-switch recombination, resulting in elevated or normal serum IgM with severely reduced IgG, IgA, and IgE levels, and susceptibility to recurrent infections due to impaired humoral and macrophage activation (PMID:8094231). The inheritance is X-linked recessive, with affected males and carrier females identified by family segregation and X-inactivation studies (PMID:9933119).

Genetic evidence includes at least 85 unique CD40LG variants reported in ≥82 unrelated male probands from >30 families, including nonsense, frameshift, splice, and missense mutations clustered in the extracellular TNF homology domain. A representative variant is c.340del (p.Gln114fs) detected in four unrelated HIGM1 patients, predicting premature truncation and absent CD40L expression (PMID:8094231). Carrier detection by PCR-SSCP and cDNA analysis has confirmed segregation in multiple pedigrees (PMID:8550833).

Functional assays consistently demonstrate loss of CD40L-CD40 interactions: mutated CD40L fails to bind CD40 in flow cytometry and ELISA, leading to defective B-cell proliferation and absence of germinal center formation. Somatic mutation analysis of immunoglobulin variable genes in patient B cells shows absence of hypermutation in most cases, with rare hypomorphic alleles permitting residual activity (PMID:8759730). Rescue experiments with wild-type CD40L restore class-switch recombination in vitro.

No credible conflicting data have been reported; polymorphic variants such as p.Gly219Arg have been shown not to cause immunodeficiency (PMID:22750225).

Integration of genetic and functional evidence yields a Definitive gene-disease association, with Strong genetic evidence and Moderate functional evidence supporting pathogenicity via haploinsufficiency. Further longitudinal studies and therapeutic gene correction are ongoing but exceed current ClinGen curation caps.

Key Take-home: CD40LG loss-of-function mutations cause X-linked HIGM1; genetic testing of CD40LG and early immunoglobulin profiling are critical for diagnosis, genetic counseling, and timely hematopoietic stem cell transplantation.

References

• Nature • 1993 • CD40 ligand mutations in x-linked immunodeficiency with hyper-IgM. PMID:8094231
• The Journal of clinical investigation • 1996 • A single strand conformation polymorphism study of CD40 ligand. PMID:8550833
• Journal of immunology • 1996 • Somatic mutations in human Ig variable genes correlate with a partially functional CD40-ligand. PMID:8759730
• Clinical genetics • 1995 • Identification of a CD40L gene mutation and genetic counselling in a family with immunodeficiency with hyperimmunoglobulinemia M. PMID:7586644
• Molecular immunology • 2012 • The polymorphism p.G219R of CD40L does not cause immunological alterations in vivo. PMID:22750225

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