STAG2-truncating variants reveal a mosaic STAG2 inactivation pattern and compensatory mechanisms involving cohesin...

Cohesin plays a central role in three-dimensional genome organization and transcriptional regulation, with functional diversity determined by incorporation of distinct STAG subunits. Pathogenic variants in the X-linked STAG2 gene cause a rare cohesinopathy with variable clinical manifestations. Molecular analyses of fibroblasts from females carrying germline STAG2-truncating variants revealed highly skewed X chromosome inactivation favoring the mutant allele, resulting in loss of STAG2 expression in most cases. STAG2-deficient cells displayed a proliferative advantage and transcriptional alterations without detectable defects in sister chromatid cohesion or DNA repair. Notably, compensatory upregulation of STAG1 and ectopic expression of the germ cell-specific paralog STAG3 were observed, leading to the formation of a previously unrecognized chimeric cohesin complex in somatic cells. These findings suggest that females with STAG2-truncating variants exhibit mosaicism for STAG2 expression and compensatory STAG3 incorporation, providing mechanistic insight into the phenotypic variability observed in STAG2-associated cohesinopathies.