Dominantly inherited combined immunodeficiency as a consequence of heterozygous germline mutations in V(D)J recombination enzymes.

Human immunodeficiencies associated with biallelic mutations in genes required for the generation of the B and T lymphocyte antigen receptors are prototypic inborn errors of immunity. We detected novel heterozygous missense mutations in critical genes implicated in the B and T cell receptor generation, termed RAG1/RAG2 and LIG4 and demonstrated that those can be associated with clinically severe immunodeficiency and immune- dysregulation. By analyzing murine models with titrable in vivo RAG activity we experimentally linked Rag gene dosage to lymphocyte development, anti-viral immunity and immune dysregulation.
Our study widens the spectrum of immunological and clinical phenotypes associated with RAG and LIG4 deficiency, which might have important implications for future molecular diagnosis and enabling effective targeted therapeutic interventions.