{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T15:40:19Z","timestamp":1787240419724,"version":"build-2736575974"},"reference-count":28,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T00:00:00Z","timestamp":1759449600000},"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>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      The transcription factors signal transducer and activator of transcription 1 and 3 (STAT1 and STAT3) play essential roles in immune and non-immune cell function. The clinical characterization of patients carrying germline gain or loss-of-function (GOF or LOF) mutations in these genes has significantly improved our understanding of their physiological and pathological roles. Although patients with\n                      <jats:italic>STAT3<\/jats:italic>\n                      LOF,\n                      <jats:italic>STAT3<\/jats:italic>\n                      GOF, and\n                      <jats:italic>STAT1<\/jats:italic>\n                      GOF mutations are classified into distinct inborn errors of immunity (IEI) categories, namely Hyper-IgE Syndrome, Regulatory T cell defects, and predisposition to Mucocutaneous Candidiasis, respectively, there is notable clinical overlap among these disorders.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Case summary<\/jats:title>\n                    <jats:p>\n                      We describe a 17-year-old girl with recurrent lung infection leading to bronchiectasis, chronic onychomycosis, recurrent vulvovaginal candidiasis, and oral thrush. Additional findings included short stature, delayed puberty, and retained primary teeth. Laboratory results revealed eosinophilia and elevated IgE serum levels, with a NIH HIES score of 53. A rare heterozygous deletion within the 3\u2032UTR of the\n                      <jats:italic>STAT3<\/jats:italic>\n                      gene (c.*351_*353del) was identified through a candidate gene approach. Although the variant is in a non-coding region, increased\n                      <jats:italic>STAT3<\/jats:italic>\n                      phosphorylation and elevated suppressor of cytokine signaling 3 (SOCS3) expressions suggested a potential GOF effect.\n                      <jats:italic>In silico<\/jats:italic>\n                      analysis further predicted that the deletion disrupts microRNA (miRNA) binding sites and RNA binding proteins (RBP), potentially impairing post-transcriptional regulation and contributing to\n                      <jats:italic>STAT3<\/jats:italic>\n                      overexpression. Given the complexity of the phenotype and the atypical location of the\n                      <jats:italic>STAT3<\/jats:italic>\n                      variation, whole-exome sequencing (WES) was performed, revealing a heterozygous missense mutation in the\n                      <jats:italic>STAT1<\/jats:italic>\n                      DNA-binding domain (\n                      <jats:italic>c.1053G&amp;gt;T<\/jats:italic>\n                      ,\n                      <jats:italic>p.L351F<\/jats:italic>\n                      ), previously reported in autosomal dominant chronic mucocutaneous candidiasis (AD-CMC). Functional assays on lymphocytes confirmed an increased\n                      <jats:italic>STAT1<\/jats:italic>\n                      phosphorylation compared to both\n                      <jats:italic>STAT1<\/jats:italic>\n                      LOF patient and healthy controls.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      This case highlights the diagnostic complexity of overlapping IEI phenotypes and the value of combining targeted and WES strategies. This dual molecular diagnosis, comprising a regulatory variant in\n                      <jats:italic>STAT3<\/jats:italic>\n                      and a pathogenic coding mutation in\n                      <jats:italic>STAT1<\/jats:italic>\n                      , emphasizes the need to include non-coding regions in genetic analyses. It also underscores the value of using techniques that offer a broader genomic view and capture all coding exons, enabling a more comprehensive correlation with the clinical and immunological phenotype.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1646761","type":"journal-article","created":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T05:29:26Z","timestamp":1759469366000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Case Report: Dual molecular diagnosis of gain-of-function STAT1 mutation and regulatory STAT3 variant in a patient with a hyper-IgE-like 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