• H S Kuehn, B Boisson, C Cunningham-Rundles, J Reichenbach, A Stray-Pedersen, E W Gelfand, P Maffucci, K R Pierce, J K Abbott, K V Voelkerding, S T South, N H Augustine, J S Bush, W K Dolen, B B Wray, Y Itan, A Cobat, H S Sorte, S Ganesan, S Prader, T B Martins, M G Lawrence, J S Orange, K R Calvo, J E Niemela, J-L Casanova, T A Fleisher, H R Hill, A Kumánovics, M E Conley, and S D Rosenzweig.
• Department of Laboratory Medicine, National Institutes of Health Clinical Center (H.S.K., K.R.C., J.E.N., T.A.F., S.D.R.), and the Primary Immunodeficiency Clinic (S.D.R.) and Biological Imaging Section, Research Technologies Branch (S.G.), National Institute of Allergy and Infectious Diseases, Bethesda, MD; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University (B.B., Y.I., A.C., J.-L.C., M.E.C.), Howard Hughes Medical Institute (J.-L.C.), and the Department of Medicine and the Immunology Institute, Icahn School of Medicine at Mount Sinai (C.C.-R., P.M.) - all in New York; the Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM Unité 1163 and Paris Descartes University, Imagine Institute, Paris (A.C., J.-L.C.); the Division of Immunology, University Children's Hospital Zurich (J.R., S.P.), Children's Research Center (J.R., S.P.), and University of Zurich (J.R.) - all in Zurich, Switzerland; the Center for Human Immunobiology, Texas Children's Hospital (A.S.-P., J.S.O.), and the Departments of Pediatrics (A.S.-P., J.S.O.) and Molecular and Human Genetics (A.S.-P.), Baylor-Hopkins Center for Mendelian Genomics, Baylor College of Medicine, Houston; the Norwegian Unit for National Newborn Screening (A.S.-P.) and the Department of Medical Genetics (H.S.S.), Oslo University Hospital, Oslo; University of Tennessee College of Medicine, Memphis (K.R.P.); the Division of Allergy and Immunology, Department of Pediatrics, National Jewish Health, Denver (E.W.G., J.K.A.); the Departments of Pathology (K.V.V., S.T.S., N.H.A., T.B.M., H.R.H., A.K.) and Pediatrics and Medicine (H.R.H.), University of Utah School of Medicine and ARUP (Associated Regional and University Pathologists) Institute for Clinical and Experimental Pathology, ARUP Laboratories (T.B.M.) - both in Salt Lake City; the Division of Allergy-Immunology and Pediatric Rheumatology, Department of Pediatrics, Medical College of Georgia, Augusta University, Augusta (J.S.B., W.K.D., B.B.W.); and the Division of Asthma, Allergy, and Immunology, Department of Medicine, University of Virginia, Charlottesville (M.G.L.).
• N. Engl. J. Med. 2016 Mar 17; 374 (11): 1032-1043.

BackgroundCommon variable immunodeficiency (CVID) is characterized by late-onset hypogammaglobulinemia in the absence of predisposing factors. The genetic cause is unknown in the majority of cases, and less than 10% of patients have a family history of the disease. Most patients have normal numbers of B cells but lack plasma cells.MethodsWe used whole-exome sequencing and array-based comparative genomic hybridization to evaluate a subset of patients with CVID and low B-cell numbers. Mutant proteins were analyzed for DNA binding with the use of an electrophoretic mobility-shift assay (EMSA) and confocal microscopy. Flow cytometry was used to analyze peripheral-blood lymphocytes and bone marrow aspirates.ResultsSix different heterozygous mutations in IKZF1, the gene encoding the transcription factor IKAROS, were identified in 29 persons from six families. In two families, the mutation was a de novo event in the proband. All the mutations, four amino acid substitutions, an intragenic deletion, and a 4.7-Mb multigene deletion involved the DNA-binding domain of IKAROS. The proteins bearing missense mutations failed to bind target DNA sequences on EMSA and confocal microscopy; however, they did not inhibit the binding of wild-type IKAROS. Studies in family members showed progressive loss of B cells and serum immunoglobulins. Bone marrow aspirates in two patients had markedly decreased early B-cell precursors, but plasma cells were present. Acute lymphoblastic leukemia developed in 2 of the 29 patients.ConclusionsHeterozygous mutations in the transcription factor IKAROS caused an autosomal dominant form of CVID that is associated with a striking decrease in B-cell numbers. (Funded by the National Institutes of Health and others.).

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