ADAR1 loss-of-function variants altering RNA editing define a new interferon-dependent psoriasis subtype

Recent evidence implicates altered RNA editing and dysregulated type I IFN signaling in immune-mediated diseases, including psoriasis, although the underlying genetic mechanisms remain poorly defined. We investigated four unrelated multiplex families with early-onset plaque psoriasis, with or without psoriatic arthritis, segregating as a monogenic trait and characterized by a strong IFN signature in skin and blood. Whole-exome sequencing identified four rare heterozygous loss-of-function mutations in ADAR1 cosegregating with disease and elevated IFN-stimulated gene expression. Six additional rare variants were detected in an independent cohort of 125 psoriasis patients. Single-cell transcriptomics identified keratinocytes and melanocytes as major IFN sources. Functional studies showed that ADAR1 knockdown or expression of ADAR1G1119R and ADAR1P3A alleles pathogenic variants reduced adenosine-to-inosine RNA editing and increased IFN-stimulated genes and inflammatory cytokines, effects reversed by upadacitinib and deucravacitinib. These findings define a novel IFN-dependent psoriasis subtype caused by inborn defects of ADAR1-mediated RNA editing, with direct implications for precision medicine in psoriatic disease.