ClinVar

In 2 brothers, born of consanguineous Pakistani parents, with pseudo-TORCH syndrome-3 (PTORCH3; 618886), Duncan et al. (2019) identified a homozygous c.442C-T transition (c.442C-T, NM_005419.3) in the STAT2 gene, resulting in an arg148-to-trp (R148W) substitution at a highly conserved residue in the coiled-coil domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was found only in the heterozygous state at a very low frequency in the gnomAD database. STAT2 protein expression was unaffected in patient cells. RNA and RT-PCR analysis of patient blood showed increased IFN-stimulated gene (ISG) gene expression, consistent with a type I interferonopathy. Patient cells and STAT2-null cells transduced with the mutation showed a similar heightened sensitivity to IFNA1 (147660), consistent with an abnormally enhanced response upon exposure to interferon, rather than constitutive activation of STAT2. The abnormalities were associated with prolonged IFNAR (107450) signaling in patient cells, but not in parental cells carrying the heterozygous mutation, which the authors noted is unusual for gain-of-function mutations. Further in vitro studies showed that the R148W mutation impaired the interaction of STAT2 with the negative regulator USP18 (607057), resulting in desensitization to the negative regulation normally conferred by USP18. The findings were consistent with an inability of patient cells to properly restrain IFNAR signaling, which results in an inflammatory disease consistent with a type I interferonopathy. Duncan et al. (2019) noted that the loss of negative regulation of IFNAR signaling, due to the STAT2 mutation, behaves as a recessive trait with an overall gain-of-function effect on the IFN signaling pathway.