Defects of B-cell terminal differentiation in patients with type-1 Kabuki syndrome

Background Kabuki syndrome (KS) is a complex multisystem developmental disorder associated with mutation of genes encoding histone-modifying proteins. In addition to craniofacial, intellectual, and cardiac defects, KS is also characterized by humoral immune deficiency and autoimmune disease, yet no detailed molecular characterization of the KS-associated immune phenotype has been reported. Objective We sought to characterize the humoral immune defects found in patients with KS with lysine methyltransferase 2D (KMT2D) mutations. Methods We comprehensively characterized B-cell function in a cohort (n = 13) of patients with KS (age, 4 months to 27 years). Results Three quarters (77%) of the cohort had a detectable heterozygous KMT2D mutation (50% nonsense, 20% splice site, and 30% missense mutations), and 70% of the reported mutations are novel. Among the patients with KMT2D mutations (KMT2D Mut/+ ) , hypogammaglobulinemia was detected in all but 1 patient, with IgA deficiency affecting 90% of patients and a deficiency in at least 1 other isoform seen in 40% of patients. Numbers of total memory (CD27+ ) and class-switched memory B cells (IgM− ) were significantly reduced in patients with KMT2D Mut/+ mutations compared with numbers in control subjects ( P