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Hum Mol Genet. 2015 Dec 20;24(25):7361-72. doi: 10.1093/hmg/ddv437. Epub 2015 Oct 16.

DCLRE1C (ARTEMIS) mutations causing phenotypes ranging from atypical severe combined immunodeficiency to mere antibody deficiency.

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Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg and University of Freiburg, Freiburg, Germany.
Institute for Transfusion Medicine, University Ulm, Ulm, Germany.
Department of Pediatric Immunology and Allergy.
Institute of Pathology, Campus Benjamin Franklin, Charité - University Medicine Berlin, Berlin, Germany.
Division of Clinical Immunology and Transfusion Medicine, Department of Laboratory Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
Department of Health and Human Services, National Center for Biotechnology Information, National Institutes of Health, Bethesda, MD, USA.
Center for Pathology, Medical Center, University of Freiburg, Freiburg, Germany.
Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center, Freiburg, Germany.
Max-Delbruck Center for Molecular Medicine, Berlin, Germany.
Science and Technology Department, BGI-Shenzhen, Shenzhen, China.
Department of Immunology and Allergy, Meram Medical Faculty, Necmettin Erbakan University, Konya, Turkey.
Institute of Human Genetics, University of Würzburg, Würzburg, Germany.
Institute for Transfusion Medicine, University Ulm, Ulm, Germany, Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service Baden-Württemberg, Hessen, Germany and.
Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg and University of Freiburg, Freiburg, Germany, Institute of Immunity and Transplantation, University College London, Royal Free Campus, London, UK


Null mutations in genes involved in V(D)J recombination cause a block in B- and T-cell development, clinically presenting as severe combined immunodeficiency (SCID). Hypomorphic mutations in the non-homologous end-joining gene DCLRE1C (encoding ARTEMIS) have been described to cause atypical SCID, Omenn syndrome, Hyper IgM syndrome and inflammatory bowel disease-all with severely impaired T-cell immunity. By whole-exome sequencing, we investigated the molecular defect in a consanguineous family with three children clinically diagnosed with antibody deficiency. We identified perfectly segregating homozygous variants in DCLRE1C in three index patients with recurrent respiratory tract infections, very low B-cell numbers and serum IgA levels. In patients, decreased colony survival after irradiation, impaired proliferative response and reduced counts of naïve T cells were observed in addition to a restricted T-cell receptor repertoire, increased palindromic nucleotides in the complementarity determining regions 3 and long stretches of microhomology at switch junctions. Defective V(D)J recombination was complemented by wild-type ARTEMIS protein in vitro. Subsequently, homozygous or compound heterozygous DCLRE1C mutations were identified in nine patients from the same geographic region. We demonstrate that DCLRE1C mutations can cause a phenotype presenting as only antibody deficiency. This novel association broadens the clinical spectrum associated with ARTEMIS mutations. Clinicians should consider the possibility that an immunodeficiency with a clinically mild initial presentation could be a combined immunodeficiency, so as to provide appropriate care for affected patients.

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