{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T04:55:42Z","timestamp":1781585742015,"version":"3.54.5"},"reference-count":11,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T00:00:00Z","timestamp":1781568000000},"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>\n                    Inborn defects of the alternative pathway (AP) of the complement system have revealed its essential role in host defense against invasive infections caused by encapsulated bacteria. Biallelic pathogenic variants in the\n                    <jats:italic>CFB<\/jats:italic>\n                    gene cause complement factor B (FB) deficiency, an exceptionally rare inborn error of immunity (IEI), with only three cases reported to date. Here, we describe a fourth case of autosomal recessive FB deficiency. An 8-month-old boy with no significant medical history presented with severe pneumococcal bacteremia with clinical and radiological features of meningoencephalitis. We performed comprehensive clinical, immunological, genetic, and functional analyses. Complement studies revealed absent AP activity with preserved classical and lectin pathway function. Quantification of individual complement components showed markedly reduced FB levels with no rise of FBb and normal concentrations of properdin, factor D (FD), factor H (FH), factor I (FI), C3 and C3d, consistent with a primary defect in FB production. Targeted genetic testing initially identified a single splice-site\n                    <jats:italic>CFB<\/jats:italic>\n                    variant (c.898-2A&amp;gt;C), but the profound alterations in the biochemical phenotype suggested a missed second\n                    <jats:italic>CFB<\/jats:italic>\n                    variant. Additional in-depth analyses using whole-exome sequencing revealed the presence of an additional non-canonical splice-site\n                    <jats:italic>CFB<\/jats:italic>\n                    variant (c.1168\u00a0+\u00a010G&amp;gt;T). RNA sequencing of patient-derived dermal fibroblasts followed by Sanger sequencing demonstrated that both variants caused aberrant splicing, including exon skipping and cryptic splice-site activation. Segregation analyses confirmed compound heterozygosity in the proband, while the heterozygous carrier of the c.1168\u00a0+\u00a010G&amp;gt;T variant showed reduced FB levels but preserved AP activity. Rescue assays functionally validated the molecular diagnosis, as AP activity could not be restored by mixing with FB-deficient serum but was rescued by supplementation with recombinant FB. This case expands the genetic spectrum of FB deficiency to include non-coding\n                    <jats:italic>CFB<\/jats:italic>\n                    variants and highlights the critical value of integrating in-depth functional immunological assays with advanced genomic and transcriptomic analyses to establish a definitive diagnosis in rare cases of IEI.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1803307","type":"journal-article","created":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T04:29:37Z","timestamp":1781584177000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Case Report: Integrated genomic and immunological assays identify non-coding CFB variants in pneumococcal meningoencephalitis"],"prefix":"10.3389","volume":"17","author":[{"given":"J.","family":"Barbieur","sequence":"first","affiliation":[{"name":"Primary Immune Deficiency Research Lab (PIRL), Department of Internal Medicine and Pediatrics, Ghent University","place":["Ghent, Belgium"]},{"name":"Center for Primary Immunodeficiency Ghent, Jeffrey Modell Diagnosis and Research Center, ERN-RITA reference center, Ghent University Hospital","place":["Ghent, Belgium"]},{"name":"Department of Pediatric Pulmonology, Immunology and Infectiology, Ghent University Hospital","place":["Ghent, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E.","family":"D\u2019haenens","sequence":"additional","affiliation":[{"name":"Center for Medical Genetics, Ghent University Hospital","place":["Ghent, Belgium"]},{"name":"Department of Biomedical Molecular Biology, Ghent University","place":["Ghent, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T.","family":"Jarayseh","sequence":"additional","affiliation":[{"name":"Primary Immune Deficiency Research Lab (PIRL), Department of Internal Medicine and Pediatrics, Ghent University","place":["Ghent, Belgium"]},{"name":"Center for Primary Immunodeficiency Ghent, Jeffrey Modell Diagnosis and Research Center, ERN-RITA reference center, Ghent University Hospital","place":["Ghent, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L.","family":"Hoste","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Ghent University Hospital","place":["Ghent, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Smet","sequence":"additional","affiliation":[{"name":"Department of Immunology, Laboratoire Hospitalier Universitaire de Bruxelles - Universitair Laboratorium Brussel (LHUB-ULB), Universit\u00e9 Libre de Bruxelles (ULB)","place":["Brussels, Belgium"]},{"name":"Immunology Department, University Hospital Brugmann, Universit\u00e9 Libre de Bruxelles (ULB)","place":["Brussels, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Lambrecht","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Ghent University Hospital","place":["Ghent, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E.","family":"Schiettecatte","sequence":"additional","affiliation":[{"name":"Department of Radiology and Nuclear Medicine, Ghent University Hospital","place":["Ghent, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P.","family":"Schelstraete","sequence":"additional","affiliation":[{"name":"Department of Pediatric Pulmonology, Immunology and Infectiology, Ghent University Hospital","place":["Ghent, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"De Bruyne","sequence":"additional","affiliation":[{"name":"Center for Medical Genetics, Ghent University Hospital","place":["Ghent, Belgium"]},{"name":"Department of Biomedical Molecular Biology, Ghent University","place":["Ghent, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F.","family":"Haerynck","sequence":"additional","affiliation":[{"name":"Primary Immune Deficiency Research Lab (PIRL), Department of Internal Medicine and Pediatrics, Ghent University","place":["Ghent, Belgium"]},{"name":"Center for Primary Immunodeficiency Ghent, Jeffrey Modell Diagnosis and Research Center, ERN-RITA reference center, Ghent University Hospital","place":["Ghent, Belgium"]},{"name":"Department of Pediatric Pulmonology, Immunology and Infectiology, Ghent University Hospital","place":["Ghent, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. J.","family":"Tavernier","sequence":"additional","affiliation":[{"name":"Primary Immune Deficiency Research Lab (PIRL), Department of Internal Medicine and Pediatrics, Ghent University","place":["Ghent, Belgium"]},{"name":"Center for Primary Immunodeficiency Ghent, Jeffrey Modell Diagnosis and Research Center, ERN-RITA reference center, Ghent University Hospital","place":["Ghent, Belgium"]},{"name":"Center for Medical Genetics, Ghent University Hospital","place":["Ghent, Belgium"]},{"name":"Department of Biomedical Molecular Biology, Ghent University","place":["Ghent, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2025.102711","article-title":"Complement deficiencies and infections","volume":"98","author":"El Sissy","year":"2025","journal-title":"Curr Opin Immunol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.70962\/jhi.20250007","article-title":"Inborn errors of immunity: manifestation, treatment, and outcome-an ESID registry 1994-2024 report on 30,628 patients","volume":"1","author":"Kindle","year":"2025","journal-title":"J Hum Immun"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc1306326","article-title":"Deficiency in complement factor B","volume":"369","author":"Slade","year":"2013","journal-title":"N Engl J Med"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-020-00906-3","article-title":"A novel case of complement factor B deficiency","volume":"41","author":"Gauthier","year":"2021","journal-title":"J ClinImmunol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1002\/eji.70148","article-title":"Meningococcal serogroup Y meningitis reveals inborn factor B deficiency","volume":"56","author":"Bougeard","year":"2026","journal-title":"Eur J Immunol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"749","DOI":"10.1016\/j.jaci.2020.08.014","article-title":"Plasma C3d levels as a diagnostic marker for complete complement factor I deficiency","volume":"147","author":"Naesens","year":"2021","journal-title":"J Allergy Clin Immunol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.adi0252","article-title":"A complement atlas identifies interleukin-6-dependent alternative pathway dysregulation as a key druggable feature of COVID-19","volume":"15","author":"Van Damme","year":"2023","journal-title":"Sci Transl Med"},{"key":"B8","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1038\/s41525-025-00502-7","article-title":"Cracking rare disorders: a new minimally invasive RNA-seq protocol","volume":"10","author":"De Cock","year":"2025","journal-title":"NPJ Genom Med"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-020-00754-1","article-title":"Deficiencies, diagnosis, and management","volume":"40","author":"Brodszki","year":"2020","journal-title":"J ClinImmunol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1001\/jamapediatrics.2019.3203","article-title":"Prevalence of immunodeficiency in children with invasive pneumococcal disease in the pneumococcal vaccine era: a systematic review","volume":"173","author":"Butters","year":"2019","journal-title":"JAMA Pediatr"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1097\/ACI.0b013e3283591534","article-title":"The 10 warning signs: a time for a change","volume":"12","author":"O\u2019Sullivan","year":"2012","journal-title":"Curr Opin Allergy Clin Immunol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1803307\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T04:29:42Z","timestamp":1781584182000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1803307\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,16]]},"references-count":11,"alternative-id":["10.3389\/fimmu.2026.1803307"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1803307","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,16]]},"article-number":"1803307"}}