We discuss pathogenic variants affecting the cleavage phase (RAG1, RAG2, and the recently identified RAG co-chaperone NudC domain-containing 3, NUDCD3), end processing (ARTEMIS), ligation and repair (LIG4, XLF, XRCC4, PRKDC), and genome surveillance pathways (ATM, MRN complex, RNF168), highlighting genotype-phenotype correlations and mechanisms driving immune deficiency and dysregulation. This evidence concerns the gene LIG4 and Immunodeficiency.