{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T08:37:23Z","timestamp":1776933443817,"version":"3.51.2"},"reference-count":20,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T00:00:00Z","timestamp":1772668800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T00:00:00Z","timestamp":1772668800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Selcuk University"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Eur J Pediatr"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Inborn errors of immunity (IEI) comprise a heterogeneous group of disorders with diverse clinical manifestations. In this study, we aimed to evaluate genetic findings in patients with suspected IEI and to assess the contribution of next-generation sequencing (NGS) in identifying both IEI-related and non-IEI-related genetic variants. Between January 2020 and January 2025, 91 pediatric patients (0\u201318\u00a0years) referred for suspected IEI were retrospectively analyzed. Demographic data, clinical features, immunological profiles, and genetic results were reviewed, including single-gene sequencing, fluorescence in situ hybridization (FISH), targeted gene panels (TGP), and whole-exome sequencing (WES). Patients analyzed by NGS were classified into three categories according to detected variants: IEI-related, non-IEI-related, and undetected disease-causing variant. A total of 79 patients underwent NGS-based genetic testing. The mean age was 4.37\u2009\u00b1\u20095.09\u00a0years. WES was performed in 40 patients (50.6%) and TGP in 39 (49.4%). Pathogenic variants linked to IEI-related were detected in 28 patients (35.4%), whereas non-IEI-related pathogenic variants were identified in 12 (15.2%). The remaining 39 patients (49.4%) had undetected disease-causing variants. The diagnoses of patients carrying pathogenic variants unrelated to IEI included primary ciliary dyskinesia, Ellis\u2013van Creveld syndrome, desmoglein-1 deficiency, and others.<\/jats:p>\n                  <jats:p>\n                    <jats:italic>Conclusion<\/jats:italic>\n                    :\u00a0Our study highlights the importance of genetic testing in the differential diagnosis of IEI and provides evidence supporting its role in identifying mixed IEI phenotypes. Comprehensive interpretation of genetic results within a multidisciplinary clinical framework is essential for accurate diagnosis, appropriate management, and effective genetic counseling.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:table-wrap>\n                      <jats:table>\n                        <jats:tbody>\n                          <jats:tr>\n                            <jats:td align=\"left\">\n                              <jats:bold>What is Known:<\/jats:bold>\n                              \u2022\n                              <jats:italic>Inborn errors of immunity are rare, genetically heterogeneous disorders with overlapping phenotypes, often causing delayed diagnosis and necessitating next-generation sequencing<\/jats:italic>\n                              .\u2022\n                              <jats:italic>Recent multicenter studies show that whole-exome sequencing has increased diagnostic yield to over 40-50% and improved clinical classification and management<\/jats:italic>\n                              .\n                            <\/jats:td>\n                          <\/jats:tr>\n                          <jats:tr>\n                            <jats:td align=\"left\">\n                              <jats:bold>What is New:<\/jats:bold>\n                              \u2022\n                              <jats:italic>Comprehensive genetic testing revealed clinically significant non\u2013IEI-related variants in 15.2% of patients with mixed or atypical IEI phenotypes<\/jats:italic>\n                              .\u2022\n                              <jats:italic>A multidisciplinary approach broadened the diagnostic perspective beyond classical IEI, enabling more accurate and individualized patient management<\/jats:italic>\n                              .\n                            <\/jats:td>\n                          <\/jats:tr>\n                        <\/jats:tbody>\n                      <\/jats:table>\n                    <\/jats:table-wrap>\n                  <\/jats:p>","DOI":"10.1007\/s00431-026-06778-w","type":"journal-article","created":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T07:06:25Z","timestamp":1772694385000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genetic analysis of children with suspected immunodeficiency: mimickers of inborn errors of immunity"],"prefix":"10.1007","volume":"185","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-7351-9612","authenticated-orcid":false,"given":"Saniye Yasemin","family":"Y\u0131lmaz","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3812-9654","authenticated-orcid":false,"given":"\u0130lknur","family":"K\u00fclha\u015f \u00c7elik","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5125-2855","authenticated-orcid":false,"given":"Ebru","family":"Marzio\u011flu \u00d6zdemir","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9807-2605","authenticated-orcid":false,"given":"Hasibe","family":"Arta\u00e7","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,3,5]]},"reference":[{"issue":"1","key":"6778_CR1","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1007\/s10875-019-00737-x","volume":"40","author":"SG Tangye","year":"2020","unstructured":"Tangye SG, Al-Herz W, Bousfiha A, Chatila T, Cunningham-Rundles C, Etzioni A et al (2020) Human inborn errors of immunity: 2019 update on the classification from the IUIS. J Clin Immunol 40(1):24\u201364","journal-title":"J Clin Immunol"},{"issue":"1","key":"6778_CR2","doi-asserted-by":"publisher","DOI":"10.70962\/jhi.20250003","volume":"1","author":"MC Poli","year":"2025","unstructured":"Poli MC, Aksentijevich I, Bousfiha A, Cunningham-Rundles C, Hambleton S, Klein C et al (2025) Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee. J Hum Immunol 1(1):e20250003. https:\/\/doi.org\/10.70962\/jhi.20250003","journal-title":"J Hum Immunol"},{"issue":"8","key":"6778_CR3","doi-asserted-by":"publisher","first-page":"954","DOI":"10.1007\/s10875-014-0102-8","volume":"34","author":"L Kobrynski","year":"2014","unstructured":"Kobrynski L, Powell RW, Bowen S (2014) Prevalence and morbidity of primary immunodeficiency diseases, United States 2001\u20132007. J Clin Immunol 34(8):954\u2013961. https:\/\/doi.org\/10.1007\/s10875-014-0102-8","journal-title":"J Clin Immunol"},{"issue":"5","key":"6778_CR4","doi-asserted-by":"publisher","first-page":"1051","DOI":"10.1007\/s10875-022-01272-y","volume":"42","author":"RE El Hawary","year":"2022","unstructured":"El Hawary RE, Meshaal SS, Abd Elaziz DS, Alkady R, Lotfy S, Eldash A et al (2022) Genetic testing in Egyptian patients with inborn errors of immunity: a single-center experience. J Clin Immunol 42(5):1051\u20131070. https:\/\/doi.org\/10.1007\/s10875-022-01272-y","journal-title":"J Clin Immunol"},{"issue":"2","key":"6778_CR5","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1111\/cei.13626","volume":"206","author":"AM Ripen","year":"2021","unstructured":"Ripen AM, Chear CT, Baharin MF, Nallusamy R, Chan KC, Kassim A et al (2021) A single-center pilot study in Malaysia on the clinical utility of whole-exome sequencing for inborn errors of immunity. Clin Exp Immunol 206(2):119\u2013128. https:\/\/doi.org\/10.1111\/cei.13626","journal-title":"Clin Exp Immunol"},{"issue":"3","key":"6778_CR6","first-page":"237","volume":"202","author":"OM Delmonte","year":"2020","unstructured":"Delmonte OM, Ricciardelli I, Bonilla FA (2020) Challenges in the diagnosis of primary immunodeficiencies: an evolving story. Clin Exp Immunol 202(3):237\u2013246","journal-title":"Clin Exp Immunol"},{"issue":"1","key":"6778_CR7","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1016\/j.jaci.2016.05.042","volume":"139","author":"A Stray-Pedersen","year":"2017","unstructured":"Stray-Pedersen A, Sorte HS, Samarakoon P, Gambin T, Chinn IK, Akdemir ZHC et al (2017) Primary immunodeficiency diseases: genomic approaches delineate heterogeneous Mendelian disorders. J Allergy Clin Immunol 139(1):232\u2013245. https:\/\/doi.org\/10.1016\/j.jaci.2016.05.042","journal-title":"J Allergy Clin Immunol"},{"issue":"10","key":"6778_CR8","doi-asserted-by":"publisher","first-page":"1197","DOI":"10.1007\/s00439-020-02199-3","volume":"139","author":"PD Stenson","year":"2020","unstructured":"Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L et al (2020) The Human Gene Mutation Database (HGMD\u00ae): optimizing its use in a clinical diagnostic or research setting. Hum Genet 139(10):1197\u20131207. https:\/\/doi.org\/10.1007\/s00439-020-02199-3","journal-title":"Hum Genet"},{"issue":"5","key":"6778_CR9","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","volume":"17","author":"S Richards","year":"2015","unstructured":"Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J et al (2015) Standards and guidelines for the \u0131nterpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17(5):405\u2013424. https:\/\/doi.org\/10.1038\/gim.2015.30","journal-title":"Genet Med"},{"issue":"7","key":"6778_CR10","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1007\/s10875-016-0314-1","volume":"36","author":"N Galal","year":"2016","unstructured":"Galal N, Meshaal S, Elhawary R, Abd ElAziz D, Alkady R, Lotfy S et al (2016) Patterns of primary immunodeficiency disorders among a highly consanguineous population: Cairo University Pediatric Hospital\u2019s 5-year experience. J Clin Immunol 36(7):649\u201355","journal-title":"J Clin Immunol"},{"issue":"7","key":"6778_CR11","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1007\/s10875-024-01759-w","volume":"44","author":"B Erman","year":"2024","unstructured":"Erman B, Aba U, Ipsir C, Pehlivan D, Aytekin C, Cildir G et al (2024) Genetic evaluation of patients with clinically diagnosed inborn errors of immunity by whole exome sequencing: results from a specialized research center for immunodeficiency in T\u00fcrkiye. J Clin Immunol 44(7):157. https:\/\/doi.org\/10.1007\/s10875-024-01759-w","journal-title":"J Clin Immunol"},{"issue":"6","key":"6778_CR12","doi-asserted-by":"publisher","first-page":"1339","DOI":"10.1007\/s10875-021-01053-z","volume":"41","author":"A Aghamohammadi","year":"2021","unstructured":"Aghamohammadi A, Rezaei N, Yazdani R, Delavari S, Kutukculer N, Topyildiz E et al (2021) Consensus Middle East and North Africa Registry on Inborn Errors of Immunity. J Clin Immunol 41(6):1339\u201351. https:\/\/doi.org\/10.1007\/s10875-021-01053-z","journal-title":"J Clin Immunol"},{"issue":"2","key":"6778_CR13","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1007\/s12098-008-0022-9","volume":"75","author":"S Verma","year":"2008","unstructured":"Verma S, Sharma PK, Sivanandan S, Rana N, Saini S, Lodha R et al (2008) Spectrum of primary immune deficiency at a tertiary care hospital. Indian J Pediatr 75(2):143\u20138. https:\/\/doi.org\/10.1007\/s12098-008-0022-9","journal-title":"Indian J Pediatr"},{"issue":"10","key":"6778_CR14","doi-asserted-by":"publisher","first-page":"885","DOI":"10.1007\/s12098-019-02971-y","volume":"86","author":"D Gupta","year":"2019","unstructured":"Gupta D, Thakral D, Kumar P, Kabra SK, Lodha R, Kumari R et al (2019) Primary immunodeficiency disorders among North Indian children. Indian J Pediatr 86(10):885\u201391. https:\/\/doi.org\/10.1007\/s12098-019-02971-y","journal-title":"Indian J Pediatr"},{"key":"6778_CR15","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.837243","volume":"13","author":"HM Shendi","year":"2022","unstructured":"Shendi HM, Al Kuwaiti AA, Al Dhaheri AD, Al-Hammadi S (2022) The spectrum of inborn errors of immunity in the United Arab Emirates: 5-year experience in a tertiary center. Front Immunol 13:837243. https:\/\/doi.org\/10.3389\/fimmu.2022.837243","journal-title":"Front Immunol"},{"issue":"2","key":"6778_CR16","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1007\/s10875-019-00613-8","volume":"39","author":"ZN Zysman-Colman","year":"2019","unstructured":"Zysman-Colman ZN, Kaspy KR, Alizadehfar R, NyKamp KR, Zariwala MA, Knowles MR et al (2019) Nasal nitric oxide in primary immunodeficiency and primary ciliary dyskinesia: helping to distinguish between clinically similar diseases. J Clin Immunol 39(2):216\u201324. https:\/\/doi.org\/10.1007\/s10875-019-00613-8","journal-title":"J Clin Immunol"},{"issue":"2","key":"6778_CR17","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1097\/ACI.0000000000001059","volume":"25","author":"I Taietti","year":"2025","unstructured":"Taietti I, Catamer\u00f2 F, Lodi L, Giovannini M, Castagnoli R (2025) Inborn errors of immunity with atopic phenotypes in the allergy and immunology clinic: a practical review. Curr Opin Allergy Clin Immunol 25(2):105\u2013114. https:\/\/doi.org\/10.1097\/ACI.0000000000001059","journal-title":"Curr Opin Allergy Clin Immunol"},{"issue":"3","key":"6778_CR18","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1007\/s12098-021-03936-w","volume":"89","author":"HP Lashkari","year":"2022","unstructured":"Lashkari HP, Madkaikar M, Dalvi A, Gupta M, Bustamante J, Sharma M et al (2022) Clinical and genetic spectrum of inborn errors of immunity in a tertiary care center in southern India. Indian J Pediatr 89(3):233\u201342. https:\/\/doi.org\/10.1007\/s12098-021-03936-w","journal-title":"Indian J Pediatr"},{"issue":"45","key":"6778_CR19","doi-asserted-by":"publisher","DOI":"10.3346\/jkms.2023.38.e387","volume":"38","author":"JK Lee","year":"2023","unstructured":"Lee JK, Oh A (2023) Combined malonic and methylmalonic aciduria diagnosed by recurrent and severe \u0131nfections mimicking a primary \u0131mmunodeficiency disease: a case report. J Korean Med Sci 38(45):e387. https:\/\/doi.org\/10.3346\/jkms.2023.38.e387","journal-title":"J Korean Med Sci"},{"key":"6778_CR20","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2024.1279112","volume":"12","author":"S von Hardenberg","year":"2024","unstructured":"von Hardenberg S, Klefenz I, Steinemann D, Di Donato N, Baumann U, Auber B et al (2024) Current genetic diagnostics in inborn errors of immunity. Front Pediatr 12:1279112. https:\/\/doi.org\/10.3389\/fped.2024.1279112","journal-title":"Front Pediatr"}],"container-title":["European Journal of Pediatrics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00431-026-06778-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00431-026-06778-w","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00431-026-06778-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T07:41:06Z","timestamp":1776930066000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00431-026-06778-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,5]]},"references-count":20,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["6778"],"URL":"https:\/\/doi.org\/10.1007\/s00431-026-06778-w","relation":{},"ISSN":["1432-1076"],"issn-type":[{"value":"1432-1076","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,5]]},"assertion":[{"value":"30 November 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 January 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 January 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 March 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Approval was obtained from the Ethics Committee of Sel\u00e7uk University Faculty of Medicine (approval number 2025\/67; meeting date February 11, 2025). The study was conducted in accordance with the Declaration of Helsinki. All participants gave informed consent before inclusion in the study.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Human ethics"}},{"value":"Written informed consent was obtained from all individual participants included in the study.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"The authors declare no competing interests.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"162"}}