Human STAT3 variants underlie autosomal dominant hyper IgE syndrome by negative dominance

Most 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, seven 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 (i) truncated proteins, (ii) neoproteins generated from a translation re-initiation codon, (iii) 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.