TABLE 2.

Summary of inter-TAD alterations (TAD shuffling, Inter-TAD loss- or gain-of-function alterations and Neo-TADs), the disease/abnormality they caused and their description.

TAD shuffling
Wnt6/Epha4 locus	F-syndrome	An inversion at the Wnt6/Epha4 locus that misplaces the Epha4 enhancers near Wnt6 gene, causing its mis-expression in the developing limb bud (Lupiáñez et al., 2015; Kraft et al., 2019)
Ihh/Epha4 locus	Polydactyly	Duplications of the previous enhancers and rearranging them in front of the Ihh gene induce overexpression of Ihh (Kraft et al., 2019)
TFAP2A locus	Branchio-oculofacial syndrome	Inversion of the TFAP2A TAD resulted in lower TFAP2A expression due to the fact that the promoter was separated from its associated enhancers (Laugsch et al., 2019)
Shh locus	Digit syndactyly	An inversion at the Shh locus places the Shh gene in a TAD together with a limb enhancer, that induces its activation (Lettice et al., 2011)
MEF2C locus	5q14.3 microdeletion syndrome	Patients with balanced MEF2C translocations have been shown to be affected by the separation of promoters from their associated enhancers. The influence of these translocations was confirmed in patient-derived LCLs, which showed lower MEF2C expression (Redin et al., 2017)
GATA2 locus	Acute myeloid leukemia sub-types	A chromosomal inversion and translocation in chromosome 3 at two different breakpoints place the GATA2 enhancer in the same TAD as the EVI1 oncogene. The enhancer is then in close proximity with the EVI1 promoter triggering its activation, which is responsible for the development of the disease (Gröschel et al., 2014)
IGF2 locus	Colorectal cancer	Recurrent tandem duplications encompassing a TAD boundary result into new interactions between IGF2 and a cell specific super-enhancer located in the adjacent TAD, leading to its > 250-fold overexpression (Weischenfeldt et al., 2017). The duplications in the abovementioned TAD boundary are tandem rather inverted or dispersed, suggesting that the orientation of the enhancer and IGF2 is probably important for the activation of IGF2 (Beroukhim et al., 2016)
Inter-TAD loss- or gain-of-function alterations
IDH locus	Gliomas	Mutations in the IDH gene results in accumulation of 2-hydroxyglutarate, which subsequently represses TET proteins. This causes hyper-methylation of CpG sites and increased methylation of CTCF sites affecting CTCF binding and the respective TAD boundaries. New interactions are consequently established between the oncogene PDGFRA with constitutive enhancers, which are normally located outside its normal TAD (Flavahan et al., 2016)
FMR1 locus	Fragile X syndrome (FXS)	The CGG triplet repeat (short tandem repeat or STRs) within the FMR1 gene expands in an erratic way and the FMR1 locus boundary is disrupted due to inability of CTCF to bound, caused by the abnormal DNA methylation levels. FMR1 is silenced as the boundary is disrupted, because of the separation from its associated regulatory elements, which are now located in another TAD (Anania and Lupiáñez, 2020).
Neo-TADs
Kcnj2 and Sox9 loci	Limb malformation	A neo-TAD where Kcnj2 interacts with the Sox9 regulatory region resulted in overexpression of Kcnj2 (Franke et al., 2016)
IGF2 locus	Cancer	Due to duplications of neighboring TADs, the new TAD incorporates the IGF2 gene and a lineage-specific super enhancer, resulting in oncogenic locus mis-regulation (Weischenfeldt et al., 2017)