Fig. 5: Fibroblasts carrying SETBP1 variants outside the degron showed distinct transcriptomic profiles from healthy controls, SGS and SETBP1-haploinsufficiency disorder patients.

a Schematic representation of the SETBP1 protein (UniProt: Q9Y6X0) indicating the locations of variants included in the RNA-seq experiment. b Fibroblasts derived from patients harbouring a SETBP1 variant (missense or in-frame deletion) outside the degron formed separate clusters from healthy controls, and partially overlapped with those from SGS and SETBP1-haploinsufficiency disorder patients. Principal component analysis (PCA) plot of variance distribution of eight control fibroblast lines (black), two lines carrying a variant within the degron (orange), six lines carrying a variant outside the degron (blue), and three lines carrying a truncating variant (purple); three technical replicates were included for all patient lines and control lines 5–8; six replicates were included for control lines 1–4. A list of cell lines included in the RNA-seq experiment can be found in Supplementary Data 5. Principal components (PC) 1 and PC2 accounted for 30% and 13% of total variance, respectively. c Volcano plots showing the gene expression data of control vs patient fibroblast lines (left: within degron; middle: outside degron; right: truncating) as a function of log ratios and mean average gene counts. The number of significant DEGs that are up- and down-regulated are shown (log₂ fold change ≥ 1 or ≤−1, p < 0.05, multiple testing correction with FDR). d Venn diagram showing the overlap of genes that demonstrated significant differential expression (p < 0.05, multiple testing correction with FDR) in control vs SGS variants within degron (orange), variants outside degron (blue) and truncating variants (purple). e Top four dysregulated GO biological processes revealed by over-representation analysis of the up- (top) and down-regulated (bottom) DEGs in patient fibroblasts carrying different SETBP1 variants (p < 0.05, multiple testing correction with FDR; orange: within degron; blue: outside degron; purple: truncating). f RRHO heatmaps showed transcriptomic overlaps between two comparisons. Bottom left corner of the heatmap indicates overlap signal from up-regulated genes in both conditions. The top right corner of the heatmap indicates an overlap signal from down-regulated genes in both conditions. Source data are provided as a Source Data file (Source Data 6–8).