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Genetic analysis confirmed the absence of the variant in population databases, and computational predictions of pathogenicity were conflicting. Functional assessment revealed that the variant\n                    <jats:italic>STAT3<\/jats:italic>\n                    Arg417Thr maintained normal DNA binding but exhibited reduced IL-6\u2013induced transcriptional activity and no negative-dominance. Further, significantly impaired STAT3-dependent, IL-10\u2013mediated suppression of TNF-\u03b1 production were found in patient-derived monocytes, consistent with a partial loss-of-function effect. Clinically, affected individuals presented with recurrent staphylococcal skin abscesses, eczema, atopic or infectious complications, and characteristic facial features. There was a marked variability in extra-hematopoietic manifestations such as retained primary teeth, vascular anomalies, and psychiatric disorders. Laboratory findings included elevated serum IgE levels, but only slightly reduced or normal Th17 cell counts. NIH-HIES scores varied within the family (range: 12\u201334), highlighting the variability of clinical expression. Based on ACMG guidelines, the variant was classified as likely pathogenic due to absence from controls, co-segregation with disease, and supportive functional evidence. This report highlights the challenges in interpreting novel\n                    <jats:italic>STAT3<\/jats:italic>\n                    variants and the critical need for functional validation in uncertain cases. The findings emphasize the importance of molecular diagnosis irrespective of clinical scoring and address the ethical complexities of genetic testing in familial disease.\n                  <\/jats:p>","DOI":"10.1007\/s10875-026-02036-8","type":"journal-article","created":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T05:56:24Z","timestamp":1780898184000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Novel Partial Loss-of-function STAT3-variant as Cause of Hyper-IgE-Syndrome in a Danish Family with Variable Expressivity"],"prefix":"10.1007","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9053-9047","authenticated-orcid":false,"given":"Camilla Heldbjerg","family":"Drabe","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9749-2598","authenticated-orcid":false,"given":"Jonathan","family":"Gehrig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5004-7822","authenticated-orcid":false,"given":"Jens Magnus Bernth","family":"Jensen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-3223-0440","authenticated-orcid":false,"given":"Mira Marie","family":"Laustsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3963-3804","authenticated-orcid":false,"given":"Carsten Schade","family":"Larsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7170-2734","authenticated-orcid":false,"given":"Camilla Darum","family":"S\u00f8rensen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3185-9611","authenticated-orcid":false,"given":"Kirstine Overgaard","family":"Dyrmose","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1298-7490","authenticated-orcid":false,"given":"Sophia","family":"Hammer-Hansen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9729-9111","authenticated-orcid":false,"given":"Jens","family":"Wittner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1604-422X","authenticated-orcid":false,"given":"Tania","family":"Masmas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9740-6522","authenticated-orcid":false,"given":"Hanne","family":"Marquart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9265-2721","authenticated-orcid":false,"given":"Stephan","family":"Ehl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1719-9856","authenticated-orcid":false,"given":"Line","family":"Borgwardt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2233-500X","authenticated-orcid":false,"given":"Terese L.","family":"Katzenstein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,8]]},"reference":[{"key":"2036_CR1","doi-asserted-by":"publisher","first-page":"1013","DOI":"10.1016\/S0140-6736(66)90119-X","volume":"287","author":"JOB\u2019S SYNDROME","year":"1966","unstructured":"JOB\u2019S SYNDROME. 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LGB: consultant and speakers fee from Chiesi Farmaceutici S.p.A. TLK: personal fees and grants, including travel grants, from ViiV\/Glaxo Smith Kline, Gilead, Merck Sharp & Dohme, CLS Behring, Takeda, Chiesi and Vertex. CSL: Consultant and speakers fee from AstraZeneca, Bavarian Nordic, CSL-Behring, GSK, Moderna, MSD, Pfizer, Takeda and Valneva.All unrelated to the current study.","order":2,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"80"}}