Immune deficiencies, infection, and systemic immune disordersDefects of B-cell terminal differentiation in patients with type-1 Kabuki syndrome

BackgroundKabuki 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.ObjectiveWe sought to characterize the humoral immune defects found in patients with KS with lysine methyltransferase 2D (KMT2D) mutations.MethodsWe comprehensively characterized B-cell function in a cohort (n = 13) of patients with KS (age, 4 months to 27 years).ResultsThree 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 (KMT2DMut/+), 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 KMT2DMut/+ mutations compared with numbers in control subjects (P < .001). Patients with KMT2DMut/+ mutations also had significantly reduced rates of somatic hypermutation in IgG (P = .003) but not IgA or IgM heavy chain sequences. Impaired terminal differentiation was noted in primary B cells from patients with KMT2DMut/+ mutations. Autoimmune pathology was observed in patients with missense mutations affecting the SET domain and its adjacent domains.ConclusionsIn patients with KS, autosomal dominant KMT2D mutations are associated with dysregulation of terminal B-cell differentiation, leading to humoral immune deficiency and, in some cases, autoimmunity. All patients with KS should undergo serial clinical immune evaluations.