The polymorphism p.G219R of CD40L does not cause immunological alterations in vivo: Conclusions from a X-linked hyper IgM syndrome kindred

Hyper-IgM syndromes (HIGM) are characterized by low levels of IgG, IgA and IgE and normal to high levels of IgM. Patients with these syndromes present recurrent infections due to an impaired immunoglobulin maturation. The most prevalent form of HIGM, X-linked hyper IgM syndrome (XHIM), is caused by mutations in the gene encoding the CD40 ligand (CD40LG). We present two siblings with XHIM caused by a large CD40LG deletion affecting more than half of the gene, and extended from the end of intron 3 to far upstream of the promoter regions. Genetic analysis in the maternal family discovered the CD40LG219R polymorphism in several members. Segregation of this polymorphism in the kindred indicated that the deletion of CD40LG was a de novo mutation in the mother. Although half of her CD4+ T cells did not express CD40L and the other half expressed the CD40LG219R variant, the mother was healthy. This suggests that this polymorphism is not pathogenic by itself although it has been recently related to X-linked lymphoproliferative syndrome.

► CD40LG deletion is responsible for X-linked hyper-IgM syndrome in two siblings.
► The patients’ mother was healthy despite expressing only the CD40LG219R variant.
► Our findings indicate that the CD40LG219R variant is not pathological by itself.