Principal Investigator King Abdullah University of Science and Technology (KAUST) Thuwal, Saudi Arabia
Abstract: Sex chromosome overdosage in Klinefelter Syndrome (KS; 47,XXY), Jacobs Syndrome (JS; 47,XYY), and high-grade sex chromosome aneuploidies (SCAs; 48,XXXY and 49,XXXXY) results in a spectrum of clinical manifestations, including intellectual disabilities and delays in motor, speech, and language development. The severity of neurological symptoms correlates with the number of supernumerary sex chromosomes; however, the in vitro modeling of these diseases remains largely unexplored. In this study, we employed an iPSC-based approach to elucidate the effects of sex chromosome aneuploidies on early neurodevelopment. Differentiation of iPSCs from individuals with KS, JS, high-grade SCAs, and 46,XY controls into neural stem cells (NSCs) and neurons revealed X chromosome dosage-sensitive impairments in NSC differentiation and survival. Neurons derived from high-grade SCAs exhibited reduced neurite branching, diminished number of MAP2-positive dendrites, and failed to establish functional networks. Integrated methylation and transcriptomic profiling of NSCs demonstrated widespread epigenomic and transcriptomic alterations in X aneuploidies, characterized by X-linked hypermethylation proportional to X chromosome dosage. In contrast, Y chromosome aneuploidy was associated with subtle epigenomic changes. We quantified gene expression changes across X and Y chromosome complements using linear regression modeling. Our analysis uncovered modular transcriptomic alterations specific to X or Y chromosomes, with ~30% of these changes shared between KS and JS. Notably, a subset of X-linked genes escaping X-inactivation, located in the pseudoautosomal (PAR) regions of X and Y chromosomes, defined both X and Y transcriptomic signatures and may contribute to the overlapping neurodevelopmental deficits observed in SCAs. To further dissect the molecular mechanisms, we developed 46,XY NSCs overexpressing individual candidate PAR genes, identifying their roles in transcriptomic dysregulation associated with aneuploidies. Additionally, we created an open-access, web-based platform to facilitate exploration of the epigenetic and transcriptomic landscapes of SCAs, offering a valuable resource for investigating the genetic basis of X and Y overdosage during early neurodevelopment.
