Sequential mosaic variants inKRASandSTAT5Bassociated with a mixed phenotype of two acquired errors of immunity

Abstract

AbstractMosaic genetic variation has been implicated in the pathogenesis of both malignant and non-malignant immunological disease. Here, we report a unique case of postnatal acquisition of a gain-of-function (GoF)KRASvariant, with an additional GoFSTAT5Bvariant, in a woman with inflammatory bowel disease, splenomegaly, thrombocytopenia, bronchiectasis, monocytosis, and eosinophilia. Targeted amplicon sequencing revealed widespread distribution of both variants in key immune cell populations, and in historical blood and tissue samples, with the emergence of both variants coinciding with the time of clinical presentation. Short- and long-read single cell RNA sequencing of patient cells highlighted a unique population of monocytes, with a broad distribution of both variants, and dysregulated cytokine signaling pathways. Flow cytometry revealed dysregulated STAT signaling, and the presence of a distinct population of highly granular CD24+ cells. Taken together with the clinical presentation, these findings led to a diagnosis of combined RAS-associated autoimmune leukoproliferative disorder (RALD) and non-clonalSTAT5BGoF disease. To our knowledge, this is the first reported combination of two distinct acquired errors of immunity causing a mixed clinical phenotype, and highlights the importance of considering acquired monogenic diseases within a broader genomic context.