In this Perspective, Bharathavikru and Hastie discuss recent studies published by Hunter et al., investigating the molecular mechanisms by which mutations in the gene encoding the RNA degradation component DIS3L2 lead to Perlman syndrome, and Chen et al., who show that microRNA processing gene mutations in Wilms tumor leads to an increase in the levels of transcription factor PLAG1 that in turn activates IGF2 expression. Here, DIS3L2 is linked to Nephroblastoma.