The RET proto-oncogene is the major gene involved in the complex genetics of 
Hirschsprung disease (HSCR), or aganglionic megacolon, showing causative 
loss-of-function mutations in 15-30% of the sporadic cases. Several RET 
polymorphisms and haplotypes have been described in association with the 
disease, suggesting a role for this gene in HSCR predisposition, also in the 
absence of mutations in the coding region. Finally, the presence of a functional 
variant in intron 1 has repeatedly been proposed to explain such findings. Here 
we report a case-control study conducted on 97 Italian HSCR sporadic patients 
and 85 population matched controls, using 13 RET polymorphisms distributed 
throughout the gene, from the basal promoter to the 3'UTR. Linkage 
disequilibrium and haplotype analyses have shown increased recombination between 
the 5' and 3' portions of the gene and an over-representation, in the cases 
studied, of two haplotypes sharing a common allelic combination that extends 
from the promoter up to intron 5. We propose that these two disease-associated 
haplotypes derive from a single founding locus, extending up to intron 19 and 
successively rearranged in correspondence with a high recombination rate region 
located between the proximal and distal portions of the gene. Our results 
suggests the possibility that a common HSCR predisposing variant, in linkage 
disequilibrium with such haplotypes, is located further downstream than the 
previously suggested interval encompassing intron 1.