Figure 1. Classical outcomes of mutation‐induced aberrant transcripts. The upper panel shows a pre‐mRNA molecule with exons (boxes) separated by introns (lines). Splice‐site consensus sequences (5′SS, 3′SS, polypyrimidine tract and BPS) are indicated for the central exon. Inactivation of the 5′SS and 3′SS sequences can lead to exon skipping (either single exon skipping or multiple exon skipping). (a,b) Activation of downstream or upstream (cryptic) splice sites; (c) Full intron retention; (d) Mutations that create strong splice sites in intronic regions can lead to pseudoexon activation.

Figure 2. Mutation‐induced aberrant transcripts following inactivation/activation of SRE elements. The aberrant transcripts originate mostly from exon skipping (a), cryptic splice site activation (b), full intron retention (c), and pseudoexon inclusion (d). Mutation in enhancer or silencer elements that led to their disruption (or creation) can lead to the same consequences described for the basic regulatory factors, with the addition that the creation of enhancers or silencer loss can lead to increased levels of exon inclusion.

Figure 3. Unexpected splicing outcomes in disease. These schematic panels show some unexpected splicing events that might be associated with the introduction of disease‐associated mutations in classical splicing signals, such as the acceptor or donor site of exons. The examples reported here have been described to occur in the TP, XPA, COL1A1, and CLN6 genes, respectively [ 102-105].