XIST as a potential chromosome therapy for autosomal trisomy syndromes

Autosomal trisomy syndromes are relatively rare genetic conditions due to chromosome-wide gene dosage imbalance rather than dysfunction of a single gene. Trisomy 13, 18, and 21 are the most common viable autosomal trisomy syndromes and the genetic basis of Patau syndrome, Edward syndrome and Down syndrome respectively. Despite advances in medical management and increasing understanding of the pathogenesis of these disorders, current therapies remain solely supportive. The presence of an extra copy of a chromosome results in widespread transcriptional dysregulation, motivating interest in approaches that address chromosome-wide imbalance rather than individual genes. X-inactive specific transcript, a long noncoding RNA responsible for the physiological X chromosome inactivation in females, has emerged as a potential tool for chromosome therapy. This review summarizes the epidemiology and genetic mechanisms of the autosomal trisomy syndromes and current translational research efforts using XIST-mediated silencing of the extra chromosome. By focusing on chromosome-wide epigenetic modulation, XIST-mediated approaches provide a conceptual framework for developing translational strategies targeting gene dosage imbalance in autosomal trisomy syndromes.