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The recent elucidation of the molecular defects leading to hyper-IgM syndromes has provided considerable insight into the complex mechanisms that govern the antibody maturation in humans.The study of a large cohort of patients revealed unexpected clinical, immunological and genetic findings, which have significant implications on the molecular basis of immunoglobulin class switch recombination and somatic hypermutation, as shown for hypomorphic mutations in the nuclear factor-κB essential modulator (NEMO) gene and peculiar activation-induced cytidine deaminase defects that differently affect class switch recombination and somatic hypermutation. The description of the hyper-IgM condition due to mutations in the gene encoding uracil-N glycosylase has been essential for defining the DNA-editing activity of activation-induced cytidine deaminase. Novel findings are awaited from the study of the yet genetically undefined hyper-IgM syndromes, leading to the identification of activation-induced cytidine deaminase cofactors and proteins involved in class switch recombination-induced DNA repair. In the genetically characterized hyper-IgM syndromes, the precise identification of the molecular defect allows the evaluation of hyper-IgM complications, and thus aids assessment of prognosis and proper survey and treatment.The important contribution made by investigation of this condition improves our understanding of the physiology of the antibody response in humans.