Objective: The transcriptional landscape of Klinefelter syndrome (KS)during early embryogenesis remains elusive. This study aimed to evaluate the impact of X chromosome overdosage in 47,XXY males induced pluripotent stem cells (iPSCs)obtained from patients with different genomic backgrounds and ethnicities. Design and method: We derived and characterized 15 iPSC lines from four Saudi 47,XXY KS patients and one Saudi 46,XY male. We performed a comparative transcriptional analysis using the Saudi KS-iPSCs and a cohort of European and North American KS-iPSCs. Results: We identified a panel of X-linked and autosomal genes commonly dysregulated in Saudi and European/North American KS-iPSCs vs 46,XY controls. Our findings demonstrate that seven PAR1 and nine non-PAR escape genes are consistently dysregulated and mostly display comparable transcriptional levels in both groups. Finally, we focused on genes commonly dysregulated in both iPSC cohorts and identified several gene-ontology categories highly relevant to KS physiopathology, including aberrant cardiac muscle contractility, skeletal muscle defects, abnormal synaptic transmission, and behavioral alterations. Conclusions: Our results indicate that a transcriptomic signature of X chromosome overdosage in KS is potentially attributable to a subset of X-linked genes sensitive to sex chromosome dosage and escaping X inactivation, regardless of the geographical area of origin, ethnicity, and genetic makeup.
Bibliographical noteFunding Information:
This work was supported by KAUST Smart Health Initiative grant REI/1/4471-01-01 to A A and baseline funding (BAS 1077-01-01) to A A.
© 2023 the author(s) Published by Bioscientifica Ltd.
- escape genes
- induced pluripotent stem cells
- Klinefelter syndrome
- pseudoautosomal region
- X chromosome
ASJC Scopus subject areas
- Internal Medicine
- Endocrinology, Diabetes and Metabolism