{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T04:58:37Z","timestamp":1773032317295,"version":"3.50.1"},"reference-count":28,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,4,11]],"date-time":"2022-04-11T00:00:00Z","timestamp":1649635200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Here we describe a novel mutation in the <jats:italic>IKZF<\/jats:italic> gene encoding IKAROS, as the cause of common variable immunodeficiency (CVID). The identification of the same defect in the <jats:italic>IKZF<\/jats:italic> gene with manifestations of asymptomatic selective IgA deficiency and chronic ITP in the father and her younger brother, respectively, demonstrates the large variability of this genetic defect in one single family, while living in the same environment with a relatively similar genetic background. As discussed, clinical penetrance of the molecular defects identified by mutations in <jats:italic>IKZF<\/jats:italic> and other common gene defects in CVID in familial immune-related abnormalities makes genetic testing a necessary step for diagnosis, management, and counseling, as part of the routine immunological workup.<\/jats:p>","DOI":"10.3389\/fimmu.2022.865838","type":"journal-article","created":{"date-parts":[[2022,4,11]],"date-time":"2022-04-11T08:20:24Z","timestamp":1649665224000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["Case Report: A Highly Variable Clinical and Immunological Presentation of IKAROS Deficiency in a Single Family"],"prefix":"10.3389","volume":"13","author":[{"given":"Taco W.","family":"Kuijpers","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samantha A. M.","family":"Tromp","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ester M. M.","family":"van Leeuwen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Godelieve J.","family":"de Bree","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,4,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1007\/s10875-019-00737-x","article-title":"Human Inborn Errors of Immunity: 2019 Update on the Classification From the International Union of Immunological Societies Expert Committee","volume":"40","author":"Tangye","year":"2020","journal-title":"J Clin Immunol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.coi.2014.05.004","article-title":"Discovery of Single-Gene Inborn Errors of Immunity by Next Generation Sequencing","volume":"30","author":"Conley","year":"2014","journal-title":"Curr Opin Immunol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1007\/s10875-017-0464-9","article-title":"International Union of Immunological Societies: 2017 Primary Immunodeficiency Diseases Committee Report on Inborn Errors of Immunity","volume":"38","author":"Picard","year":"2018","journal-title":"J Clin Immunol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2018.01.039","article-title":"Loss-Of-Function Nuclear Factor kappaB Subunit 1 (NFKB1) Variants Are the Most Common Monogenic Cause of Common Variable Immunodeficiency in Europeans","volume":"142","author":"Tuijnenburg","year":"2018","journal-title":"J Allergy Clin Immunol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-019-00656-x","article-title":"Diagnostic Yield of Next Generation Sequencing in Genetically Undiagnosed Patients With Primary Immunodeficiencies: A Systematic Review","volume":"39","author":"Yska","year":"2019","journal-title":"J Clin Immunol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2265-1","article-title":"Whole-Genome Sequencing of a Sporadic Primary Immunodeficiency Cohort","volume":"583","author":"Thaventhiran","year":"2020","journal-title":"Nature"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2021.06.010","article-title":"Inborn Errors of IKAROS and AIOLOS","volume":"72","author":"Yamashita","year":"2021","journal-title":"Curr Opin Immunol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/nri747","article-title":"Haematopoietic Cell-Fate Decisions, Chromatin Regulation and Ikaros","volume":"2","author":"Georgopoulos","year":"2002","journal-title":"Nat Rev Immunol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2020007292","article-title":"Germline IKAROS Dimerization Haploinsufficiency Causes Hematologic Cytopenias and Malignancies","volume":"137","author":"Kuehn","year":"2021","journal-title":"Blood"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20211118","article-title":"T and B Cell Abnormalities, Pneumocystis Pneumonia, and Chronic Lymphocytic Leukemia Associated With an AIOLOS Defect in Patients","volume":"218","author":"Kuehn","year":"2021","journal-title":"J\u00a0Exp Med"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.clim.2014.10.003","article-title":"Primary Immunodeficiencies in the Netherlands: National Patient Data Demonstrate the Increased Risk of Malignancy","volume":"156","author":"Jonkman-Berk","year":"2015","journal-title":"Clin Immunol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2013.12.1077","article-title":"Clinical Picture and Treatment of 2212 Patients With Common Variable Immunodeficiency","volume":"134","author":"Gathmann","year":"2014","journal-title":"J Allergy Clin Immunol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2015-103690","article-title":"Genes Associated With Common Variable Immunodeficiency: One Diagnosis to Rule Them All","volume":"53","author":"Bogaert","year":"2016","journal-title":"J Med Genet"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2018.02.055","article-title":"Phenotype, Penetrance, and Treatment of 133 Cytotoxic T-Lymphocyte Antigen 4-Insufficient Subjects","volume":"142","author":"Schwab","year":"2018","journal-title":"J Allergy Clin Immunol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/bs.ai.2020.02.001","article-title":"Homeostatic and Pathogenic Roles of PI3Kdelta in the Human Immune System","volume":"146","author":"Sogkas","year":"2020","journal-title":"Adv Immunol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"432","DOI":"10.1016\/j.jaci.2017.08.019","article-title":"A Novel IKAROS Haploinsufficiency Kindred With Unexpectedly Late and Variable B-Cell Maturation Defects","volume":"141","author":"Bogaert","year":"2018","journal-title":"J Allergy Clin Immunol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2017.25","article-title":"Germline IKAROS Mutation Associated With Primary Immunodeficiency That Progressed to T-Cell Acute Lymphoblastic Leukemia","volume":"31","author":"Yoshida","year":"2017","journal-title":"Leukemia"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1512234","article-title":"Loss of B Cells in Patients With Heterozygous Mutations in IKAROS","volume":"374","author":"Kuehn","year":"2016","journal-title":"N Engl J Med"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1172\/JCI98164","article-title":"Dominant-Negative IKZF1 Mutations Cause a T, B, and Myeloid Cell Combined Immunodeficiency","volume":"128","author":"Boutboul","year":"2018","journal-title":"J Clin Invest"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2019.00139","article-title":"Familial Immune Thrombocytopenia Associated With a Novel Variant in IKZF1","volume":"7","author":"Sriaroon","year":"2019","journal-title":"Front Pediatr"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00568","article-title":"Assessing the Functional Relevance of Variants in the IKAROS Family Zinc Finger Protein 1 (IKZF1) in a Cohort of Patients With Primary Immunodeficiency","volume":"10","author":"Eskandarian","year":"2019","journal-title":"Front Immunol"},{"key":"B22","doi-asserted-by":"publisher","first-page":"699","DOI":"10.1016\/j.jaci.2018.04.008","article-title":"A Kindred With Mutant IKAROS and Autoimmunity","volume":"142","author":"Van Nieuwenhove","year":"2018","journal-title":"J Allergy Clin Immunol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"937","DOI":"10.1016\/j.ccell.2018.03.021","article-title":"Germline Genetic IKZF1 Variation and Predisposition to Childhood Acute Lymphoblastic Leukemia","volume":"33","author":"Churchman","year":"2018","journal-title":"Cancer Cell"},{"key":"B24","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s10875-020-00936-x","article-title":"IKAROS-Associated Diseases in 2020: Genotypes, Phenotypes, and Outcomes in Primary Immune Deficiency\/Inborn Errors of Immunity","volume":"41","author":"Kuehn","year":"2021","journal-title":"J Clin Immunol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2019.03.025","article-title":"Allogeneic Hematopoietic Stem Cell Transplant Outcomes for Patients With Dominant Negative IKZF1\/IKAROS Mutations","volume":"144","author":"Kellner","year":"2019","journal-title":"J Allergy Clin Immunol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-17-0465","article-title":"Recommendations for Childhood Cancer Screening and Surveillance in DNA Repair Disorders","volume":"23","author":"Walsh","year":"2017","journal-title":"Clin Cancer Res"},{"key":"B27","doi-asserted-by":"publisher","first-page":"7335","DOI":"10.1038\/ncomms8335","article-title":"Monozygotic Twins Discordant for Common Variable Immunodeficiency Reveal Impaired DNA Demethylation During Naive-to-Memory B-Cell Transition","volume":"6","author":"Rodriguez-Cortez","year":"2015","journal-title":"Nat Commun"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-018-0574-z","article-title":"Autoimmunity and Inflammation in CVID: A Possible Crosstalk Between Immune Activation, Gut Microbiota, and Epigenetic Modifications","volume":"39","author":"Jorgensen","year":"2019","journal-title":"J Clin Immunol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.865838\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,11]],"date-time":"2022-04-11T08:20:29Z","timestamp":1649665229000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.865838\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,11]]},"references-count":28,"alternative-id":["10.3389\/fimmu.2022.865838"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.865838","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,11]]},"article-number":"865838"}}