Influence of X-Chromosome Inactivation in Pathogenesis of Turner Syndrome

Turner syndrome (TS), a disorder caused by the complete or partial absence of an X chromosome, exhibits significant clinical variability that cannot be fully explained by chromosomal anomalies alone. This narrative review highlights the crucial role of epigenetic mechanisms, particularly X-chromosome inactivation (XCI), in shaping the TS phenotype. The haploinsufficiency of genes that normally escape XCI is a primary driver of TS features. The specific epigenetic consequences depend on the chromosomal anomaly. In complete monosomy (45,X), the absence of escape-mediated dosage compensation genes from a second X chromosome amplifies haploinsufficiency across X-linked escape genes. Isochromosome Xq (i(Xq)) variants involve the loss of the short arm (Xp) and duplication of the long arm (Xq), creating a dual dosage imbalance with extreme XCI skewing. Carriers of i(Xq) also have a heightened risk for autoimmune disorders compared to those with 45,X TS. For ring-X chromosomes (r(X)), which are mitotically unstable, the functional status of the XIST gene is critical. If the ring is XIST-negative, it remains transcriptionally active, resulting in functional disomy and a more severe phenotype with pronounced neurodevelopmental and craniofacial features. Ultimately, the clinical heterogeneity in TS arises from a complex interplay of the specific chromosomal structure, tissue-specific mosaicism, XIST function, and variable escape from XCI, defining TS as a disorder of epigenetic and gene-regulatory imbalance. However, future research requires a better understanding of the complex mechanism of X-chromosome inactivation.