{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T02:24:56Z","timestamp":1793413496257,"version":"4.5.0"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,11,17]],"date-time":"2021-11-17T00:00:00Z","timestamp":1637107200000},"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:sec><jats:title>Introduction<\/jats:title><jats:p>Autoimmune disorders, IgA deficiency, and allergies seem to be common among individuals with 18q deletion syndrome [OMIM 601808]. We aimed to determine the prevalence, mechanism, and genetic background of autoimmunity, immune deficiency, and allergy in a cohort of patients with 18q deletions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Material and Methods<\/jats:title><jats:p>Medical registries and social media were used to recruit the patients. Microarray oligonucleotide comparative genomic hybridization (aCGH) (Agilent, Santa Clara, CA, USA) was performed in all patients to identify size and location of chromosome 18 deletion. Clinical evaluation and medical record collection were performed in each of the study participants. The history of autoimmune disorders, severe and\/or recurrent infections, and symptoms of allergy were noted. Total immunoglobulin IgG, IgA, IgM, IgE, and IgG<jats:sub>1-4<\/jats:sub> serum levels were measured using nephelometry and ELISA methods. Lymphocyte T subset phenotyping was performed in 24 subjects from 18q del cohort. To predict the most promising candidate genes, we used the ENDEAVOUR\u2014a free web resource for gene prioritization.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>18q deletion was confirmed by means of array CGH analysis in 27 individuals, 15 (55.6%) females and 12 males, referred to the project by specialists in medical genetics, diabetology, or pediatric endocrinology between May 2015 and December 2019. The mean age at examination was 11.8 years (min\u2013max: 4.0\u201333.5). Autoimmune disorders were present in 14\/27 (51.8%) of the cohort. In eight of patients, symptoms of immune deficiency coexisted with autoimmunity. Allergy was reported in nine of 27 (33.4%) patients. Over 89% of patients presented with at list one type of immunoglobulin (IgA, IgM, IgG, IgE, and IgG<jats:sub>1-4<\/jats:sub>) deficiency and eight of 25 (32%) had abnormalities in at least two major immunoglobulin (IgG, IgA, IgM) measurements (CVID-like phenotype). Patients with 18q del exhibited a significantly decreased CD4, Treg FOXP3+, TregFOXP3+Helios+, and TemCD4 cell numbers in comparison with the control groups of 24 T1DM patients and 28 healthy controls.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Patients with 18q deletions frequently suffer from autoimmune disorders, recurrent infections, and allergy due to immune dysregulation presenting with variable antibody deficiencies and T-regulatory cell deficiency (CD4+CD25+CD127lowFOXP3+). The spectrum of speculations regarding which gene might be responsible for such phenotype ranges from single gene haploinsufficiency to deletion of a cluster of immunogenes located distally to 18q21.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2021.742834","type":"journal-article","created":{"date-parts":[[2021,11,17]],"date-time":"2021-11-17T04:32:08Z","timestamp":1637123528000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":18,"title":["Immune Dysregulation in Patients With Chromosome 18q Deletions\u2014Searching for Putative Loci for Autoimmunity and Immunodeficiency"],"prefix":"10.3389","volume":"12","author":[{"given":"Anna","family":"Hogendorf","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maciej","family":"Zieli\u0144ski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Constantinou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"\u015amigiel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jolanta","family":"Wierzba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krystyna","family":"Wyka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"W\u0119drychowicz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Jakubiuk-Tomaszuk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edyta","family":"Budzynska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malgorzata","family":"Piotrowicz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beata S.","family":"Lipska-Zi\u0119tkiewicz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ewa","family":"Kaczorowska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agata","family":"Cie\u015blikowska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Kutkowska-Ka\u017amierczak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jolanta","family":"Fijak-Moskal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monika","family":"Kugaudo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ma\u0142gorzata","family":"Kosi\u0144ska-Urba\u0144ska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnieszka","family":"Szadkowska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maciej","family":"Borowiec","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maciej","family":"Nied\u017awiecki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piotr","family":"Trzonkowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wojciech","family":"M\u0142ynarski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,11,17]]},"reference":[{"key":"B1","article-title":"Partial Deletion of the Long Arm of the Chromosome 18","volume":"12","author":"De Grouchy","year":"1964","journal-title":"Pathol Biol"},{"key":"B2","article-title":"Endocrinologic Disorders in Deletion of Chromosome 18","volume":"140","author":"Andler","year":"1992","journal-title":"Monatsschr Kinderheilkd"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1002\/(sici)1096-8628(19990827)85:5<455::aid-ajmg5>3.0.co;2-z","article-title":"Congenital Anomalies and Anthropometry of 42 Individuals With Deletions of Chromosome 18q","volume":"85","author":"Cody","year":"1999","journal-title":"Am J Med Genet"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.32899","article-title":"Narrowing Critical Regions and Determining Penetrance for Selected 18q- Phenotypes","author":"Cody","year":"2009","journal-title":"Am J Med Genet A"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.31446","article-title":"Consequences of Chromsome18q Deletions","volume":"169","author":"Cody","year":"2015","journal-title":"Am J Med Genet C Semin Med Genet"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1111\/pedi.12235","article-title":"Chromosome 18q Deletion Syndrome With Autoimmune Diabetes Mellitus: Putative Genomic Loci for Autoimmunity and Immunodeficiency","volume":"17","author":"Hogendorf","year":"2016","journal-title":"Pediatr Diabetes"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2005.04.064","article-title":"Autoimmune Thyroiditis in 18q Deletion Syndrome","volume":"147","author":"Lomenick","year":"2005","journal-title":"J Pediatr"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1001\/jama.1982.03330110055029","article-title":"Pernicious Anemia, 18q Deletion Syndrome, and IgA Deficiency","volume":"248","author":"Stricker","year":"1982","journal-title":"JAMA"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1515\/jpem.2005.18.4.419","article-title":"18q Deletion Syndrome Associated With Autoimmune Thyroid Disease Presenting as Hyperthyroidism","volume":"18","author":"Tutunculer","year":"2005","journal-title":"J Pediatr Endocrinol Metab"},{"key":"B10","article-title":"Warto\u015bci Referencyjne St\u0119\u017ce\u0144 Immunoglobulin G, A, M I D W Surowicy Zdrowych Dzieci I Os\u00f3b Doros\u0142ych, Mieszka\u0144c\u00f3w Wojew\u00f3dztwa Mazowieckiego","volume":"7","author":"Piatosa","year":"2010","journal-title":"Standardy Medyczne"},{"key":"B11","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1097\/WOX.0b013e318211496c","article-title":"World Allergy Organization Guidelines for the Assessment and Management of Anaphylaxis","volume":"4","author":"Simons","year":"2011","journal-title":"World Allergy Organ J"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaip.2019.02.004","article-title":"The European Society for Immunodeficiencies (ESID) Registry Working Definitions for the Clinical Diagnosis of Inborn Errors of Immunity","volume":"7","author":"Seidel","year":"2019","journal-title":"J Allergy Clin Immunol Pract"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.2500\/aap.2014.35.3734","article-title":"Selective IgE Deficiency, Immune Dysregulation, and Autoimmunity","volume":"35","author":"Magen","year":"2014","journal-title":"Allergy Asthma Proc"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw365","article-title":"Candidate Gene Prioritization With Endeavour","volume":"44","author":"Tranchevent","year":"2016","journal-title":"Nucleic Acids Res"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2014.00058","article-title":"SOCS, Inflammation, and Autoimmunity","volume":"3","author":"Yoshimura","year":"2012","journal-title":"Front Immunol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1111\/cei.13522","article-title":"Defective Bcl-2 Expression in Memory B Cells From Common Variable Immunodeficiency Patients","volume":"203","author":"Del Pino Molina","year":"2021","journal-title":"Clin Exp Immunol"},{"key":"B17","article-title":"Bcl-2 Deficiency in Mice Leads to Pleiotropic Abnormalities: Accelerated Lymphoid Cell Death in Thymus and Spleen, Polycystic Kidney, Hair Hypopigmentation, and Distorted Small Intestine","volume":"55","author":"Kamada","year":"1995","journal-title":"Cancer Res"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)80065-m","article-title":"Bcl-2-Deficient Mice Demonstrate Fulminant Lymphoid Apoptosis, Polycystic Kidneys, and Hypopigmented Hair","volume":"75","author":"Veis","year":"1993","journal-title":"Cell"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2015.104","article-title":"MALT1 is an Intrinsic Regulator of Regulatory T Cells","volume":"24","author":"Br\u00fcstle","year":"2017","journal-title":"Cell Death Differ"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/s1074-7613(03)00293-0","article-title":"Differential Requirement for Malt1 in T and B Cell Antigen Receptor Signaling","volume":"19","author":"Ruland","year":"2003","journal-title":"Immunity"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2013.04.047","article-title":"A Homozygous Mucosa-Associated Lymphoid Tissue 1 (MALT1) Mutation in a Family With Combined Immunodeficiency","volume":"132","author":"Jabara","year":"2013","journal-title":"J Allergy Clin Immunol"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/imm.12076","article-title":"SMAD Regulatory Networks Construct a Balanced Immune System","volume":"139","author":"Malhotra","year":"2013","journal-title":"Immunology"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2020.1752979","article-title":"Autophagy-Related Protein PIK3C3\/VPS34 Controls T Cell Metabolism and Function","volume":"17","author":"Yang","year":"2021","journal-title":"Autophagy"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2009.09.043","article-title":"Ubiquitin Ligase Nedd4L Targets Activated Smad2\/3 to Limit TGF-Beta Signaling","volume":"36","author":"Gao","year":"2009","journal-title":"Mol Cell"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00629","article-title":"The RANKL-RANK Axis: A Bone to Thymus Round Trip","volume":"10","author":"Sobacchi","year":"2019","journal-title":"Front Immunol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20062497","article-title":"RANK Signals From CD4(+)3(-) Inducer Cells Regulate Development of Aire-Expressing Epithelial Cells in the Thymic Medulla","volume":"204","author":"Rossi","year":"2007","journal-title":"J Exp Med"},{"key":"B27","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1016\/j.ajhg.2008.06.015","article-title":"Human Osteoclast-Poor Osteopetrosis With Hypogammaglobulinemia Due to TNFRSF11A (RANK) Mutations","volume":"83","author":"Guerrini","year":"2008","journal-title":"Am J Hum Genet"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1203870109","article-title":"Dependence on Nuclear Factor of Activated T-Cells (NFAT) Levels Discriminates Conventional T Cells From Foxp3+ Regulatory T Cells","volume":"109","author":"Vaeth","year":"2012","journal-title":"Proc Natl Acad Sci USA"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1111\/exd.14157","article-title":"Decreased Suppression of CD8(+) and CD4(+) T Cells by Peripheral Regulatory T Cells in Generalized Vitiligo Due to Reduced NFATC1 and FOXP3 Proteins","volume":"29","author":"Giri","year":"2020","journal-title":"Exp Dermatol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.17.9785","article-title":"Transcriptional Activating Activity of Smad4: Roles of SMAD Hetero-Oligomerization and Enhancement by an Associating Transactivator","volume":"95","author":"Shioda","year":"1998","journal-title":"Proc Natl Acad Sci USA"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.176.4.2389","article-title":"B Cell-Specific Deficiency for Smad2 In Vivo Leads to Defects in TGF-Beta-Directed IgA Switching and Changes in B Cell Fate","volume":"176","author":"Klein","year":"2006","journal-title":"J Immunol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1111\/j.1744-313X.2007.00652.x","article-title":"Mapping Susceptibility Gene Locus for IgA Deficiency at Del(18)(Q22.3-Q23); Report of Familial Cryptic Chromosome T(18q; 10p) Translocations","volume":"34","author":"Dostal","year":"2007","journal-title":"Int J Immunogenet"},{"key":"B33","first-page":"998","article-title":"Another Patient With Chromosome 18 Deletion Syndrome and Juvenile Rheumatoid Arthritis","volume":"31","author":"Rosen","year":"2004","journal-title":"J Rheumatol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1093\/omcr\/omy076","article-title":"Atrial Septal Defect can be Easily Missed in Chromosome 18q Deletion Syndrome","author":"Sabouni","year":"2018","journal-title":"Oxf Med Case Rep"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.aller.2015.07.007","article-title":"Humoral Deficiency in Three Paediatric Patients With Genetic Diseases","volume":"44","author":"Calvo Campoverde","year":"2016","journal-title":"Allergol Immunopathol (Madr)"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.31072","article-title":"18q Deletions: Clinical, Molecular, and Brain MRI Findings of 14 Individuals","volume":"140","author":"Linnankivi","year":"2006","journal-title":"Am J Med Genet A"},{"key":"B37","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1007\/s00439-013-1364-6","article-title":"Establishing a Reference Group for Distal 18q-: Clinical Description and Molecular Basis","volume":"133","author":"Cody","year":"2014","journal-title":"Hum Genet"},{"key":"B38","article-title":"Conversion of Selective IgA Deficiency to Common Variable Immunodeficiency in an Adolescent Female With 18q Deletion Syndrome","volume":"156","author":"Slyper","year":"1997","journal-title":"Eur J Pediatr"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-018-0476-0","article-title":"Low Serum IgE is a Sensitive and Specific Marker for Common Variable Immunodeficiency (CVID)","volume":"38","author":"Lawrence","year":"2018","journal-title":"J Clin Immunol"},{"key":"B40","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1186\/s13601-020-00335-w","article-title":"AllergoOncology: Ultra-Low IgE, a Potential Novel Biomarker in Cancer-a Position Paper of the European Academy of Allergy and Clinical Immunology (EAACI)","volume":"10","author":"Ferastraoaru","year":"2020","journal-title":"Clin Transl Allergy"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.15406\/moji.2014.01.00010","article-title":"Is it Hyper IgE Syndrome or Something Else","volume":"1","author":"Yasharpour","year":"2014","journal-title":"MOJ Immunol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1186\/1476-7961-8-3","article-title":"Regulation and Dysregulation of Immunoglobulin E: A Molecular and Clinical Perspective","volume":"8","author":"Pate","year":"2010","journal-title":"Clin Mol Allergy"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1038\/83713","article-title":"The Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked Syndrome (IPEX) is Caused by Mutations of FOXP3","volume":"27","author":"Bennett","year":"2001","journal-title":"Nat Genet"},{"key":"B44","doi-asserted-by":"publisher","first-page":"692","DOI":"10.1056\/NEJM199903043400904","article-title":"Hyper-IgE Syndrome With Recurrent Infections\u2013an Autosomal Dominant Multisystem Disorder","volume":"340","author":"Grimbacher","year":"1999","journal-title":"N Engl J Med"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2018.10.026","article-title":"Tregopathies: Monogenic Diseases Resulting in Regulatory T-Cell Deficiency","volume":"142","author":"Cepika","year":"2018","journal-title":"J Allergy Clin Immunol"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1200792","article-title":"Helios Induces Epigenetic Silencing of IL2 Gene Expression in Regulatory T Cells","volume":"190","author":"Baine","year":"2013","journal-title":"J Immunol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2012.03.005","article-title":"Thymic Epithelial Cells: Working Class Heroes for T Cell Development and Repertoire Selection","volume":"33","author":"Anderson","year":"2012","journal-title":"Trends Immunol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1038\/ng1297-393","article-title":"Positional Cloning of the APECED Gene","volume":"17","author":"Nagamine","year":"1997","journal-title":"Nat Genet"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1038\/ng1601","article-title":"TACI is Mutant in Common Variable Immunodeficiency and IgA Deficiency","volume":"37","author":"Castigli","year":"2005","journal-title":"Nat Genet"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00636","article-title":"Evaluating the Genetics of Common Variable Immunodeficiency: Monogenetic Model and Beyond","volume":"9","author":"de Valles-Ib\u00e1\u00f1ez","year":"2018","journal-title":"Front Immunol"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1016\/j.clim.2018.10.005","article-title":"Hypogammaglobulinemia With Decreased Class-Switched B-Cells and Dysregulated T-Follicular-Helper Cells in IPEX Syndrome","volume":"197","author":"Shamriz","year":"2018","journal-title":"Clin Immunol"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.32900","article-title":"High Resolution Genomic Analysis of 18q- Using Oligo-Microarray Comparative Genomic Hybridization (aCGH)","author":"Heard","year":"2009","journal-title":"Am J Med Genet A"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.176.4.2389","article-title":"B cell-specific deficiency for Smad2 in vivo leads to defects in TGF-beta-directed IgA switching and changes in B cell fate","volume":"176","author":"Klein","year":"2006","journal-title":"J Immunol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.742834\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,17]],"date-time":"2021-11-17T04:32:15Z","timestamp":1637123535000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.742834\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,17]]},"references-count":53,"alternative-id":["10.3389\/fimmu.2021.742834"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.742834","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,17]]},"article-number":"742834"}}