Amorphic mutations in the recombination activating genes RAG1 and RAG2 have been reported to cause T–B– SCID, whereas hypomorphic mutations led to the expansion of a few autoimmune T cell clones responsible for the Omenn syndrome phenotype. We report here a novel clinical and immunological phenotype associated with recessive RAG1 hypomorphic mutations in 4 patients from 4 different families. The immunological phenotype consists of the oligoclonal expansion of TCRγδ T cells combined with TCRαβ T cell lymphopenia. The clinical phenotype consists of severe, disseminated CMV infection and autoimmune blood cell manifestations. Repertoire studies suggest that CMV infection, in the setting of this particular T cell immunodeficiency, may have driven the TCRγδ T cell clonal expansion. This observation extends the range of clinical and immunological phenotypes associated with RAG mutations, emphasizing the role of the genetic background and microbial environment in determining disease phenotype.
Jean-Pierre de Villartay, Annick Lim, Hamoud Al-Mousa, Sophie Dupont, Julie Déchanet-Merville, Edith Coumau-Gatbois, Marie-Lise Gougeon, Arnaud Lemainque, Céline Eidenschenk, Emmanuelle Jouanguy, Laurent Abel, Jean-Laurent Casanova, Alain Fischer, Françoise Le Deist