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N Engl J Med. 2015 Jun 18;372(25):2409-22. doi: 10.1056/NEJMoa1413462.

Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections.

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From the Division of Immunology (K.D., J.C., S.K., M.J.M., K.C., K.F., T.A.C., R.S.G., L.D.N.) and Manton Center for Orphan Disease Research (L.D.N.), Boston Children's Hospital, and Department of Molecular Biology, Massachusetts General Hospital (T.K.O.), Boston, Harvard Stem Cell Institute, Harvard University, Cambridge (L.D.N.), and Department of Pediatrics, University of Massachusetts Medical School, Worcester (A.M.C.) - all in Massachusetts; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences (C.D.C., I.B., N.K.S., M.S., C.B., K.B.), Department of Pediatrics and Adolescent Medicine, Medical University of Vienna (K.B.), and CeRUD Vienna Center for Rare and Undiagnosed Diseases (K.B.) - all in Vienna; St. Giles Laboratory of Human Genetics of Infectious Disease, Rockefeller Branch, Rockefeller University (S.-Y.Z., M.A., S.O., B.B., Y.I., L.A., J.-L.C.), and Institute for Genomic Medicine, Columbia University (S. Petrovski, D.B.G.) - both in New York; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM Unité 1163 (S.-Y.Z., V.P., L.A., J.-L.C.), Paris Descartes University, Sorbonne Paris Cité, Imagine Institute (S.-Y.Z., F.R., P.L., L.A., J.-L.C.), and Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children (J.-L.C.) - all in Paris; Howard Hughes Medical Institute, Chevy Chase, MD (J.-L.C.); Department of Molecular and Translational Medicine, University of Brescia, Brescia (S. Parolini, O.P., G.T.), and Department of Experimental Medicine and Center of Excellence for Biomedical Research, University of Genoa, Genoa (A.M.) - both in Italy; Folkhälsan Institute of Genetics and Research Programs Unit, Molecular Neurology (E.H.), Institute for Molecular Medicine Finland (J.S.), Children's Hospital (M.K.), Research Programs Unit, Diabetes and Obesity Research Program (M.K.), and Folkhälsan Research Center (M.K.), University of Helsinki and Helsinki University Central Hospital, Helsinki, Tampere Center


Background Combined immunodeficiencies are marked by inborn errors of T-cell immunity in which the T cells that are present are quantitatively or functionally deficient. Impaired humoral immunity is also common. Patients have severe infections, autoimmunity, or both. The specific molecular, cellular, and clinical features of many types of combined immunodeficiencies remain unknown. Methods We performed genetic and cellular immunologic studies involving five unrelated children with early-onset invasive bacterial and viral infections, lymphopenia, and defective T-cell, B-cell, and natural killer (NK)-cell responses. Two patients died early in childhood; after allogeneic hematopoietic stem-cell transplantation, the other three had normalization of T-cell function and clinical improvement. Results We identified biallelic mutations in the dedicator of cytokinesis 2 gene (DOCK2) in these five patients. RAC1 activation was impaired in the T cells. Chemokine-induced migration and actin polymerization were defective in the T cells, B cells, and NK cells. NK-cell degranulation was also affected. Interferon-α and interferon-λ production by peripheral-blood mononuclear cells was diminished after viral infection. Moreover, in DOCK2-deficient fibroblasts, viral replication was increased and virus-induced cell death was enhanced; these conditions were normalized by treatment with interferon alfa-2b or after expression of wild-type DOCK2. Conclusions Autosomal recessive DOCK2 deficiency is a new mendelian disorder with pleiotropic defects of hematopoietic and nonhematopoietic immunity. Children with clinical features of combined immunodeficiencies, especially with early-onset, invasive infections, may have this condition. (Supported by the National Institutes of Health and others.).

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