Monoclonal gammopathies are associated with advancing age but a familial predisposition has been recognized for several decades. A functional phenotype, characterized by increased immunoglobulin (Ig) production after mitogen stimulation has been identified in healthy members of 4 families showing a predisposition toward IgM and IgG/IgA disorders. B cells from these hyperresponders do not show increased rates of Ig gene translocations and no aberrations were detected in an in vitro model of the germinal center reaction. Array-based comparative genome hybridization revealed deletions of Ig genes in peripheral blood B cells, as expected. In addition, random changes were detected throughout the genome, presumably reflecting off-target activation-induced cytidine deaminase (AID) activity. These random changes were significantly less prevalent in B cells from hyperresponders, indicating less exposure to the germinal center environment during maturation.