CD40LG genotype does not correlate with clinical phenotype in X-linked hyper-IgM syndrome

Abstract

IntroductionCD40 ligand is expressed on follicular helper T cells and binds to CD40 on B cells and antigen presenting cells (APC). The CD40L-CD40 interaction is integral to germinal center formation, immunoglobulin class switching and affinity maturation, as well as APC mediated cytokine secretion required for an effective T cell response. Patients with mutations in the CD40LG gene develop X-linked Hyper-IgM (XHIGM) syndrome characterized by recurrent sinopulmonary, opportunistic infections, liver disease and malignancy. Early studies identified no clear genotype/phenotype correlation; but a milder phenotype has been reported associated with certain variants such as T254M. PurposeTo understand if specific genetic mutations in CD40LG correlate with disease severity we developed a clinical severity scoring system and retrospectively analyzed the relationship between severity and genotype in 109 individuals with XHIGM. ResultsThe majority of reported mutations were missense (41%), splice site (27%), nonsense (13%) or deletion (13%) mutations. There was not a statistically significant difference in severity or survival among mutation type groups. We identified 10 unrelated individuals with amino acid substitution T254M and found a range of clinical phenotypes from mild disease with late onset to early manifestations, liver disease and death due to cholangiocarcinoma. ConclusionOur data confirms the lack of genotype/phenotype correlation in XHIGM and suggest the need to develop a clinical scoring system that would allow for better understanding of an individual prognostic outcome.