Asano, T.Khourieh, J.Zhang, P.Rapaport, F.Spaan, A. N.Li, J.Lei, W. T.Pelham, S. J.Hum, D.Chrabieh, M.Han, J. E.Guérin, A.Mackie, J.Gupta, S.Saikia, B.Baghdadi, J. E. I.Fadil, I.Bousfiha, A.Habib, T.Marr, N.Ganeshanandan, L.Peake, J.Droney, L.Williams, A.Celmeli, F.Hatipoglu, N.Özçelik, TayfunPicard, C.2022-02-072022-02-072021-06-170022-1007http://hdl.handle.net/11693/77122Most patients with autosomal dominant hyper-IgE syndrome (AD-HIES) carry rare heterozygous STAT3 variants. Only six of the 135 in-frame variants reported have been experimentally shown to be dominant negative (DN), and it has been recently suggested that eight out-of-frame variants operate by haploinsufficiency. We experimentally tested these 143 variants, 7 novel out-of-frame variants found in HIES patients, and other STAT3 variants from the general population. Strikingly, all 15 out-of-frame variants were DN via their encoded (1) truncated proteins, (2) neoproteins generated from a translation reinitiation codon, and (3) isoforms from alternative transcripts or a combination thereof. Moreover, 128 of the 135 in-frame variants (95%) were also DN. The patients carrying the seven non-DN STAT3 in-frame variants have not been studied for other genetic etiologies. Finally, none of the variants from the general population tested, including an out-of-frame variant, were DN. Overall, our findings show that heterozygous STAT3 variants, whether in or out of frame, underlie AD-HIES through negative dominance rather than haploinsufficiency.EnglishHuman disease geneticsImmunodeficiencyInfectious disease and host defenseInnate immunity and inflammationArticle10.1084/jem.202025921540-9538