CLINICAL EXAMPLE: INTRA-TAD DUPLICATIONS (Page 20)

; [What happens when enhancer elements at the IHH locus are duplicated within a TAD?]

Duplications of enhancer elements at the IHH locus that occur within topologically associating domains (intra-TAD) cause tissue-specific misregulation of IHH expression, associated with preaxial synpolydactyly of the feet.

; [What is synpolydactyly?]

A joint presentation of syndactyly (fusion of digits) and polydactyly (supernumerary digits).

; [What are examples of gain-of-function enhancer duplications?]

• SOX9 locus: duplications of gonad enhancer cause 46,XX sex reversal  • BCL6 locus: duplications of super enhancers cause B cell lymphomas  • SHH locus: duplications of limb enhancer causes polydactyly

; [What are examples of loss-of-function enhancer deletions?]

• PAX6 locus: aniridia  • DLX5 and/or DLX6 loci: split hand foot malformation  • SOX9 locus: deletions of gonad enhancer cause 46,XY sex reversal