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Recent advances in understanding spatial genome organization inside the nucleus have shown that chromatin is compartmentalized into megabase-scale units known as topologically associating domains (TADs). In further studies, TADs were linked to differing transcriptional activity, suggesting that they might provide a scaffold for gene regulation by promoting enhancer-promoter interaction and by insulating regulatory activities. One strong argument for this hypothesis was provided by the effects of disease-causing structural variations in congenital disease and cancer. By rearranging TADs, these mutations result in a rewiring of enhancer-promoter contacts, consecutive gene misexpression, and ultimately disease. However, not all rearrangements are equally effective in creating these effects. Here, we review several recent studies aiming to understand the mechanisms by which disease-causing mutations achieve gene misregulation. We will discuss which regulatory effects are to be expected by different disease mutations and how this new knowledge can be used for diagnostics in the clinic.