An iPSC-based model of 47,XYY Jacobs syndrome reveals a DNA methylation-independent transcriptional dysregulation shared with male X aneuploid cells

Y and X Chromosome aneuploidies contribute differently to PAR gene overexpression. (A) Schematic of 46,XY, 47,XYY, and 47,XXY fibroblasts and iPSC cohort analyzed in the present study. Fibroblasts from four males, three JS, and eight KS patients have been used to derive eight 46,XY, nine 47,XYY, and 20 47,XXY independent iPSC clones. (B) Moving average line plot (LOESS fit, span 0.45) along the X Chromosome showing the Log₂FC from control 46,XY iPSCs. Gray vertical boxes indicate PAR1 and PAR2 regions. The gray horizontal line represents no theoretical deviations from control 46,XY samples. (C,D) Venn diagram showing overlapping X-linked DEGs in the 47,XYY versus 46,XY (blue circle) and 47,XXY versus 46,XY (pink circle) contrasts in fibroblasts (C) and iPSCs (D). FDR < 0.05 and Log₂FC > |0.58|. (E) Log₂FC of detected PAR genes in 47,XYY and 47,XXY versus controls, fibroblasts (top), and iPSCs (bottom). (F) Box plot of PAR gene expression in 46,XY, 47,XXY, and 47,XYY iPSCs. (TMM) Trimmed mean of M-values. Each purple dot represents an independent RNA sample. The significance of the comparison between 47,XXY and 47,XYY versus 46,XY was calculated using the one-way ANOVA and pairwise comparison with post hoc Tukey HSD. (**) P-value < 0.01; (***) P-value < 0.001; (ns) not significant.