{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T15:56:23Z","timestamp":1753890983091,"version":"3.41.2"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,2]],"date-time":"2025-06-02T00:00:00Z","timestamp":1748822400000},"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>Background<\/jats:title><jats:p>Hyper-IgM syndrome (HIGM) is a genetic immunodeficiency characterized by elevated to normal IgM levels and decreased IgG, IgA, and IgE. The overlapping clinical presentations of different gene mutations complicate diagnosis and management.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>This study aims to elucidate the clinical implications of concurrent <jats:italic>AICDA<\/jats:italic> and <jats:italic>IKBKB<\/jats:italic> homozygous variants in a pediatric patient diagnosed with hyper-IgM syndrome.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We present immunological and genetic analysis of a Tunisian patient with two homozygous variants of uncertain significance (VUSs) in the <jats:italic>IKBKB<\/jats:italic> and <jats:italic>AICDA<\/jats:italic> genes, suspected of causing hyper-IgM and immune deficiency. We conducted functional tests to ascertain the pathogenicity of <jats:italic>IKBKB<\/jats:italic> and <jats:italic>AICDA<\/jats:italic> mutations and to provide a definitive diagnosis and appropriate management.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Genetic analysis identified two homozygous variants: <jats:italic>AICDA<\/jats:italic> (p.W80S) and <jats:italic>IKBKB<\/jats:italic> (p.R77Q). Immunophenotyping and functional studies found greatly reduced class-switched memory B cells and somatic hypermutations but normal T cell responses and NFkB activation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The simultaneous presence of multiple homozygous VUSs emphasizes a major challenge in the genetic diagnosis of highly consanguinous patients. Functional workup as well as familial segregation studies are needed to clarify variant pathogenicity and provide a definitive diagnosis and tailored treatment strategies for these patients. Our studies suggest that the <jats:italic>AICDA<\/jats:italic> p.W80S variant is pathogenic, while the <jats:italic>IKBKB<\/jats:italic> p.R77Q variant is likely benign.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1594636","type":"journal-article","created":{"date-parts":[[2025,6,2]],"date-time":"2025-06-02T05:22:14Z","timestamp":1748841734000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Dual variants of uncertain significance in a case of hyper-IgM syndrome: implications for diagnosis and 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