Novel Partial Loss-of-function STAT3-variant as Cause of Hyper-IgE-Syndrome in a Danish Family with Variable Expressivity.

Abstract

A novel heterozygous missense variant in STAT3 (NM_139276.3: c.1250G > C, NP_644805.1: p.(Arg417Thr) was identified in a Danish family spanning five generations with diverse phenotypes consistent with autosomal dominant STAT3-Hyper-IgE-Syndrome (STAT3-HIES). Genetic analysis confirmed the absence of the variant in population databases, and computational predictions of pathogenicity were conflicting. Functional assessment revealed that the variant STAT3 Arg417Thr maintained normal DNA binding but exhibited reduced IL-6-induced transcriptional activity and no negative-dominance. Further, significantly impaired STAT3-dependent, IL-10-mediated suppression of TNF-α 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: 12-34), 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 STAT3 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.