{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T20:30:04Z","timestamp":1792873804586,"version":"4.5.0"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,5,5]],"date-time":"2023-05-05T00:00:00Z","timestamp":1683244800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Purpose<\/jats:title><jats:p>Though copy number variants (CNVs) have been suggested to play a significant role in inborn errors of immunity (IEI), the precise nature of this role remains largely unexplored. We sought to determine the diagnostic contribution of CNVs using genome-wide chromosomal microarray analysis (CMA) in children with IEI.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We performed exome sequencing (ES) and CMA for 332 unrelated pediatric probands referred for evaluation of IEI. The analysis included primary, secondary, and incidental findings.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Of the 332 probands, 134 (40.4%) received molecular diagnoses. Of these, 116\/134 (86.6%) were diagnosed by ES alone. An additional 15\/134 (11.2%) were diagnosed by CMA alone, including two likely <jats:italic>de novo<\/jats:italic> changes. Three (2.2%) participants had diagnostic molecular findings from both ES and CMA, including two compound heterozygotes and one participant with two distinct diagnoses. Half of the participants with CMA contribution to diagnosis had CNVs in at least one non-immune gene, highlighting the clinical complexity of these cases. Overall, CMA contributed to 18\/134 diagnoses (13.4%), increasing the overall diagnostic yield by 15.5% beyond ES alone.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Pairing ES and CMA can provide a comprehensive evaluation to clarify the complex factors that contribute to both immune and non-immune phenotypes. Such a combined approach to genetic testing helps untangle complex phenotypes, not only by clarifying the differential diagnosis, but in some cases by identifying multiple diagnoses contributing to the overall clinical presentation.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2023.1172004","type":"journal-article","created":{"date-parts":[[2023,5,5]],"date-time":"2023-05-05T05:57:11Z","timestamp":1683266231000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["Chromosomal microarray analysis supplements exome sequencing to diagnose children with suspected inborn errors of immunity"],"prefix":"10.3389","volume":"14","author":[{"given":"Breanna J.","family":"Beers","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morgan N.","family":"Similuk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajarshi","family":"Ghosh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryce A.","family":"Seifert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leila","family":"Jamal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Kamen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael R.","family":"Setzer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colleen","family":"Jodarski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rylee","family":"Duncan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Devin","family":"Hunt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madison","family":"Mixer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjia","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weimin","family":"Bi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Veltri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Karlins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingwen","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiwen","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew J.","family":"Oler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen","family":"Jevtich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunting","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haley","family":"Hullfish","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bibiana","family":"Bielekova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela","family":"Frischmeyer-Guerrerio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"An","family":"Dang Do","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laryssa A.","family":"Huryn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth N.","family":"Olivier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen C.","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan J.","family":"Lyons","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christa S.","family":"Zerbe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V. Koneti","family":"Rao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael D.","family":"Keller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra F.","family":"Freeman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven M.","family":"Holland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis M.","family":"Franco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena A.","family":"Walkiewicz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,5,5]]},"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","DOI":"10.1007\/s12016-022-08933-1","article-title":"Diagnostic modalities in primary immunodeficiency","volume":"63","author":"Raymond","year":"2022","journal-title":"Clinic Rev Allerg Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.jped.2020.11.007","article-title":"Inborn errors of immunity: how to diagnose them","volume":"97","author":"Grumach","year":"2021","journal-title":"Jornal Pediatria"},{"key":"B4","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1186\/s41232-021-00159-6","article-title":"Inborn errors of immunity\u2013recent advances in research on the pathogenesis","volume":"41","author":"Yamashita","year":"2021","journal-title":"Inflammation Regeneration."},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-018-0012-x","article-title":"Clinical implications of systematic phenotyping and exome sequencing in patients with primary antibody deficiency","volume":"21","author":"Abolhassani","year":"2019","journal-title":"Genet Med"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2015.12.1310","article-title":"Unbiased targeted next-generation sequencing molecular approach for primary immunodeficiency diseases","volume":"137","author":"Al-Mousa","year":"2016","journal-title":"J Allergy Clin Immunol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-06-583260","article-title":"Autoimmune and other cytopenias in primary immunodeficiencies: pathomechanisms, novel differential diagnoses, and treatment","volume":"124","author":"Seidel","year":"2014","journal-title":"Blood"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2021.04.005","article-title":"Molecular diagnosis of childhood immune dysregulation, polyendocrinopathy, and enteropathy, and implications for clinical management","volume":"149","author":"Baxter","year":"2022","journal-title":"J Allergy Clin Immunol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaip.2018.12.017","article-title":"Mechanism-based precision therapy for the treatment of primary immunodeficiency and primary immunodysregulatory diseases","volume":"7","author":"Leiding","year":"2019","journal-title":"J Allergy Clin Immunology: In Practice."},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-018-0489-8","article-title":"Use of genetic testing for primary immunodeficiency patients","volume":"38","author":"Heimall","year":"2018","journal-title":"J Clin Immunol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1016\/j.jaci.2019.09.009","article-title":"Diagnostic interpretation of genetic studies in patients with primary immunodeficiency diseases: A working group report of the primary immunodeficiency diseases committee of the American academy of allergy, asthma & immunology","volume":"145","author":"Chinn","year":"2020","journal-title":"J Allergy Clin Immunol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2015.04.049","article-title":"Practice parameter for the diagnosis and management of primary immunodeficiency","volume":"136","author":"Bonilla","year":"2015","journal-title":"J Allergy Clin Immunol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.anai.2019.08.016","article-title":"Practical approach to genetic testing for primary immunodeficiencies","volume":"123","author":"Chinen","year":"2019","journal-title":"Ann Allergy Asthma Immunol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2016.05.042","article-title":"Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous mendelian disorders","volume":"139","author":"Stray-Pedersen","year":"2017","journal-title":"J Allergy Clin Immunol"},{"key":"B15","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":"B16","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2019000929","article-title":"Current genetic landscape in common variable immune deficiency","volume":"135","author":"Abolhassani","year":"2020","journal-title":"Blood"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2014.14601","article-title":"Molecular findings among patients referred for clinical whole-exome sequencing","volume":"312","author":"Yang","year":"2014","journal-title":"JAMA"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2022.06.009","article-title":"Clinical exome sequencing of 1000 families with complex immune phenotypes: Towards comprehensive genomic evaluations","author":"Similuk","year":"2022","journal-title":"J Allergy Clin Immunol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0905506","article-title":"Combined immunodeficiency associated with DOCK8 mutations","volume":"361","author":"Zhang","year":"2009","journal-title":"New Engl J Med"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2011.4013","article-title":"Copy number variation of the gene NCF1 is associated with rheumatoid arthritis","volume":"16","author":"Olsson","year":"2012","journal-title":"Antioxid Redox Signal"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2021005835","article-title":"The contribution of rare copy number variants in FAS towards pathogenesis of autoimmune lymphoproliferative syndrome","volume":"6","author":"Jevtich","year":"2022","journal-title":"Blood Adv"},{"key":"B22","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1038\/s41525-018-0053-8","article-title":"Meta-analysis of the diagnostic and clinical utility of genome and exome sequencing and chromosomal microarray in children with suspected genetic diseases","volume":"3","author":"Clark","year":"2018","journal-title":"NPJ Genom Med"},{"key":"B23","doi-asserted-by":"publisher","first-page":"897","DOI":"10.1080\/1744666X.2020.1814145","article-title":"A 2020 update on the use of genetic testing for patients with primary immunodeficiency","volume":"16","author":"Chinn","year":"2020","journal-title":"Expert Rev Clin Immunol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1111\/cei.12421","article-title":"Vaccine-associated varicella and rubella infections in severe combined immunodeficiency with isolated CD4 lymphocytopenia and mutations in IL7R detected by tandem whole exome sequencing and chromosomal microarray","volume":"178","author":"Bayer","year":"2014","journal-title":"Clin Exp Immunol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet Med"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-019-0686-8","article-title":"Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American college of medical genetics and genomics (ACMG) and the clinical genome resource (ClinGen)","volume":"22","author":"Riggs","year":"2020","journal-title":"Genet Med"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41525-020-00150-z","article-title":"Genomic testing in 1019 individuals from 349 Pakistani families results in high diagnostic yield and clinical utility","volume":"5","author":"Cheema","year":"2020","journal-title":"NPJ Genom Med"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-022-01276-8","article-title":"Copy number analysis in a Large cohort suggestive of inborn errors of immunity indicates a wide spectrum of relevant chromosomal losses and gains","volume":"42","author":"Wan","year":"2022","journal-title":"J Clin Immunol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1009723","article-title":"The impact of age on genetic risk for common diseases","volume":"17","author":"Jiang","year":"2021","journal-title":"PloS Genet"},{"key":"B30","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1111\/jop.12792","article-title":"Copy number variation: A prognostic marker for young patients with squamous cell carcinoma of the oral tongue","volume":"48","author":"Gu","year":"2019","journal-title":"J Oral Pathol Med"},{"key":"B31","unstructured":"PhenoTips"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky1105","article-title":"Expansion of the human phenotype ontology (HPO) knowledge base and resources","volume":"47","author":"K\u00f6hler","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2016.190","article-title":"Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American college of medical genetics and genomics","volume":"19","author":"Kalia","year":"2017","journal-title":"Genet Med"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-021-01171-4","article-title":"Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2021 update: a policy statement of the American college of medical genetics and genomics (ACMG)","volume":"23","author":"Miller","year":"2021","journal-title":"Genet Med"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1097\/GIM.0b013e31816b4420","article-title":"Bacterial artificial chromosome-emulation oligonucleotide arrays for targeted clinical array-comparative genomic hybridization analyses","volume":"10","author":"Ou","year":"2008","journal-title":"Genet Med"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-022-01289-3","article-title":"Human inborn errors of immunity: 2022 update on the classification from the international union of immunological societies expert committee","volume":"42","author":"Tangye","year":"2022","journal-title":"J Clin Immunol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1002\/humu.10212","article-title":"Human gene mutation database (HGMD): 2003 update","volume":"21","author":"Stenson","year":"2003","journal-title":"Hum Mutat"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2287-8","article-title":"A structural variation reference for medical and population genetics","volume":"581","author":"Collins","year":"2020","journal-title":"Nature"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2017.01.017","article-title":"Who\u2019s who? detecting and resolving sample anomalies in human DNA sequencing studies with peddy","volume":"100","author":"Pedersen","year":"2017","journal-title":"Am J Hum Genet"},{"key":"B40","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1038\/nature15393","article-title":"A global reference for human genetic variation","volume":"526","author":"Auton","year":"2015","journal-title":"Nature"},{"key":"B41","volume-title":"R: A language and environment for statistical computing","year":"2022"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2012.169","article-title":"American College of medical genetics and genomics: standards and guidelines for documenting suspected consanguinity as an incidental finding of genomic testing","volume":"15","author":"Rehder","year":"2013","journal-title":"Genet Med"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1002\/mgg3.1132","article-title":"Clinical and genetic data of 22 new patients with SMAD3 pathogenic variants and review of the literature","volume":"8","author":"Chesneau","year":"2020","journal-title":"Mol Genet Genomic Med"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-093019-124513","article-title":"Genetics of pediatric immune-mediated diseases and human immunity","volume":"39","author":"Schmitt","year":"2021","journal-title":"Annu Rev Immunol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-021-01037-z","article-title":"Genetic mosaicism as a cause of inborn errors of immunity","volume":"41","author":"Aluri","year":"2021","journal-title":"J Clin Immunol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1172004\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,5]],"date-time":"2023-05-05T05:57:14Z","timestamp":1683266234000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1172004\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,5]]},"references-count":45,"alternative-id":["10.3389\/fimmu.2023.1172004"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2023.1172004","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,5]]},"article-number":"1172004"}}