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The major genetic risk factors for Hirschsprung disease (HSCR) are three common polymorphisms within  cis -regulatory elements (CREs) of the receptor tyrosine kinase gene  RET , which reduce its expression during enteric nervous system (ENS) development. These risk variants attenuate binding of the transcription factors RARB, GATA2, and SOX10 to their cognate CREs, reduce  RET  gene expression, and dysregulate other ENS and HSCR genes in the  RET–EDNRB  gene regulatory network (GRN). Here, we use siRNA, ChIP, and CRISPR-Cas9 deletion analyses in the SK-N-SH cell line to ask how many additional HSCR-associated risk variants reside in  RET  CREs that affect its gene expression. We identify 22 HSCR-associated variants in candidate  RET  CREs, of which seven have differential allele-specific in vitro enhancer activity, and four of these seven affect  RET  gene expression; of these, two enhancers are bound by the transcription factor PAX3. We also show that deleting multiple variant-containing enhancers leads to synergistic effects on  RET  gene expression. These, coupled with our prior results, show that common sequence variants in at least 10  RET  enhancers affect HSCR risk, seven with experimental evidence of affecting  RET  gene expression, extending the known  RET–EDNRB  GRN to reveal an extensive regulatory code modulating disease risk at a single gene.

A multi-enhancer RET regulatory code is disrupted in Hirschsprung disease