In this study, we rescue synthetic lethality from Xlf and Mri by inactivating one or two alleles of Trp53. We also show that both Xlf-/-Mri-/-Trp53+/- and Xlf-/-Paxx-/-Trp53+/- mice possess a leaky SCID phenotype with severely reduced mature B and T lymphocyte counts in the spleen, low mature T cell counts in the thymus, and accumulated progenitor B cells in the bone marrow. Here, CYREN is linked to severe combined immunodeficiency.