TABLE 4.
Summary of intra-TAD alterations (loss-of-function alterations), the disease/abnormality they caused and their description.
| Intra-TAD loss-of-function alterations | ||
| Shh locus | Preaxial polydactyly (PPD) | In the ZRS, two ETV4/ETV5 binding sites have been discovered. In transgenics, a single ETV binding site is sufficient to suppress ectopic expression; the absence of both sites leads in repressor activity loss and, as a result, in ectopic Shh expression in the limb bud (Lettice et al., 2012) |
| PAX6 locus | Aniridia | Point mutations (disruption of binding sites) in enhancers of PAX6, PTF1A and TBX5 impair the expression of these genes. While it has not been demonstrated properly, these studies suggest that these point mutations impair the chromatin looping between these enhancers and their associated promoters (Smemo et al., 2012; Bhatia et al., 2013; Weedon et al., 2014) |
| PTF1A locus | Pancreatic agenesis | |
| TBX5 locus | Congenital heart disease | |
| SOX9 locus | Campomelic dysplasia | Sex reversal occurs when the relevant testis enhancer of SOX9 is deleted, while deletions and point mutations further upstream induce the Pierre-Robin syndrome, which is characterized by cranial skeleton growth defects but normal sexual development (Benko et al., 2011) |
| DYNC1I1 locus | Split-hand/split-foot malformation (SHFM) | Exons 15 and 17 of DYNC1I1 act as tissue specific limb enhancers of DLX5/6. Enhancer deletions in the DYNC1I1 gene result in down regulation of the DLX5/6 genes about 1Mb away (Allen et al., 2014; Tayebi et al., 2014) |
| ATOH7 locus | Non-syndromic congenital retinal non-attachment (NCRNA) | A deletion that covers a distal cis regulatory element upstream from ATOH7 is responsible for NCRNA (Ghiasvand et al., 2011) |
| SHH locus | Holoprosencephaly (HPE) | The loss of function (disruption of binding sites) of Shh brain enhancer-2 (SBE2) in the hypothalamus of transgenic mouse embryos was caused by a rare nucleotide variant upstream of SHH gene found in an individual with HPE (Jeong et al., 2008) |
| MYC locus | Cleft lip with or without cleft palate (CL/P) | Deletion of a 640-kb non-coding region at 8q24, which contains distal cis-acting enhancers that regulate Myc expression in the developing face, causes modest facial morphological changes in mice and, on rare occasions, CL/P (Uslu et al., 2014) |
| BCL11A locus | β-hemoglobinopathies | A common variant in an erythroid enhancer of BCL11A is associated with reduced TF binding, modestly diminished BCL11A expression, and elevated HbF (Bauer et al., 2013) |