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

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 <i>STAG2</i> gene cause a rare cohesinopathy with variable clinical manifestations. Molecular analyses of fibroblasts from females carrying germline <i>STAG2</i>-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 <i>STAG1</i> and ectopic expression of the germ cell-specific paralog <i>STAG3</i> were observed, leading to the formation of a previously unrecognized chimeric cohesin complex in somatic cells. These findings suggest that females with <i>STAG2</i>-truncating variants exhibit mosaicism for STAG2 expression and compensatory STAG3 incorporation, providing mechanistic insight into the phenotypic variability observed in <i>STAG2</i>-associated cohesinopathies.