Extended Data Fig. 1: Mis-splicing in DM1 prefrontal cortex.
a, Differential AS analysis in DM1 (N = 21) compared to control (CTRL; N = 8) prefrontal cortex. The percentage of mis-spliced AS events (left) and genes (right) in the DM1. b, Strong positive correlation between DMPK-CTG lengths and mean |ΔPSI| for mis-spliced retained intron (RI) events. Note, the 90th percentile of DMPK-CTG length was selected, since it displays the strongest correlation between repeat sizes and splicing dysregulation score in DM135. The black diagonal line represents the linear regression line, and the light gray area indicates the 95% confidence interval. P-value for a two-tailed test. c, Negative correlation between mean ΔPSI for mis-spliced RI events (n = 158) and their host transcript relative steady-state levels (baseMean ≥ 1) in DM1. FC-fold change. The black diagonal line represents the linear regression line, and the light gray area indicates the 95% confidence interval. P-value for a two-tailed test. d, Circular RNA species in CSTPP1 intron 7 (I7) in DM1 (N = 21) and CTRL (N = 8) prefrontal cortex as well as control and HeLa treated with RNase R RNA-seq samples35,92. Box plot shows I7 relative to exon 7 (E7) RNA-seq read count. Box plot shows the lower, middle, and upper quartiles. Whiskers show minimum and maximum. Two-tailed Mann-Whitney test; **P = 0.0098. e, ASD-relevant gene set enrichment analysis for mis-spliced genes in DM1 (N = 21). Diamonds represent the OR. Error bars depict the 95% confidence interval. *FDR < 0.05, **FDR < 0.01, ****FDR < 0.0001. f, Sashimi plots of DM1 (N = 8) and CTRL (N = 8) RNA-seq samples for SHANK2 miE. g, Positive correlation between DMPK-CTG lengths and mean |ΔPSI| for mis-spliced MSSNG-2017 and MSSNG-2022 genes in DM1. The black diagonal lines represent the linear regression lines, and the light gray areas indicate the 95% confidence intervals. P-value for a two-tailed test. h, Prediction of MBNL binding to mis-spliced SE events in ASD-risk genes in DM1. i, RBFOX1, RBFOX2, and RBFOX3 expression in DM1 (N = 21) and CTRL (N = 8) prefrontal cortex. Data are presented as mean values ± SD. DEseq2; nsPadj > 0.05, *Padj = 0.021. j, Differential AS analysis in RBFOX1 KD (N = 5) compared to control (N = 5) primary human neural progenitor (PHNP) cell RNA-seq samples52. The percentage of mis-spliced AS events (left) and genes (right).
