title: Defects of B-cell terminal differentiation in patients with type-1 Kabuki syndrome.
abstract: 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 < .001). Patients with KMT2D(Mut/+) 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 KMT2D(Mut/+) mutations. Autoimmune pathology was observed in patients with missense mutations affecting the SET domain and its adjacent domains.
  
  
  CONCLUSIONS
  In 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.
authors.affiliation: Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio. Electronic address: andrew.lindsley@cchmc.org.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Lindsley
authors.affiliation: Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio; Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Howard M
authors.initials: HM
authors.lastname: Saal
authors.affiliation: Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio; Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Burrow
authors.affiliation: Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio; Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Hopkin
authors.affiliation: Division of Genetics, Stead Department of Pediatrics, University of Iowa Hospitals and Clinics, Iowa City, Iowa.
authors.forename: Oleg
authors.initials: O
authors.lastname: Shchelochkov
authors.affiliation: Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio; Division of Bone Marrow Transplantation, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Pooja
authors.initials: P
authors.lastname: Khandelwal
authors.affiliation: Division of Biostatistics and Bioinformatics, Department of Environmental Health, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Changchun
authors.initials: C
authors.lastname: Xie
authors.affiliation: Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio; Division of Bone Marrow Transplantation, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Jack
authors.initials: J
authors.lastname: Bleesing
authors.affiliation: Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio; Division of Bone Marrow Transplantation, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Lisa
authors.initials: L
authors.lastname: Filipovich
authors.affiliation: Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Risma
authors.affiliation: Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Amal H
authors.initials: AH
authors.lastname: Assa'ad
authors.affiliation: Division of Pediatric Hematology/Oncology, University of North Carolina, Chapel Hill, NC.
authors.forename: Phillip A
authors.initials: PA
authors.lastname: Roehrs
authors.affiliation: Division of Immunology, Allergy and Rheumatology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Bernstein
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000276:immunology*; D000293:Adolescent; D000328:Adult; D000361:Agammaglobulinemia / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology; D002454:Cell Differentiation; D002648:Child; D002675:Child, Preschool; D004268:DNA-Binding Proteins / Q000235:genetics*; D005145:Face / Q000002:abnormalities*; D006402:Hematologic Diseases / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D007223:Infant; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D015837:Vestibular Diseases / Q000235:genetics* / Q000276:immunology*; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; C120898:KMT2D protein, human; D009363:Neoplasm Proteins
keywords: AICDA; AID; CD21(lo) B cells; KDM6A; KMT2D; Kabuki syndrome; PTIP; class-switch recombination; hypogammaglobulinemia; memory B cells; polymerase eta; somatic hypermutation