Hirschsprung disease (HSCR) is a common, multigenic neurocristopathy 
characterized by incomplete innervation along a variable length of the gut. The 
pivotal gene in isolated HSCR cases, either sporadic or familial, is RET. HSCR 
also presents in various syndromes, including Shah-Waardenburg syndrome (WS), 
Down (DS), and Bardet-Biedl (BBS). Here, we report 3 families with BBS and HSCR 
with concomitant mutations in BBS genes and regulatory RET elements, whose 
functionality is tested in physiologically relevant assays. Our data suggest 
that BBS mutations can potentiate HSCR predisposing RET alleles, which by 
themselves are insufficient to cause disease. We also demonstrate that these 
genes interact genetically in vivo to modulate gut innervation, and that this 
interaction likely occurs through complementary, yet independent, pathways that 
converge on the same biological process.