To date, three genes have been identified as susceptibility genes for 
Hirschsprung's disease (HSCR), the RET proto-oncogene, the endothelin-B receptor 
gene (EDNRB) and the endothelin-3 gene (EDN3). However, the question of whether 
these genes play a role in sporadically occurring HSCR has not been fully 
clarified. In this study, the authors performed mutation analysis of these three 
genes in 41 sporadic HSCR patients without any family history by using 
single-strand conformational polymorphism or denaturing gradient gel 
electrophoresis methods. Exon 2, 3, 5, 6, 12, 13, 15, and 17 of the RET gene, 7 
exons of the EDNRB gene, and the region of the EDN3 gene including sequences 
corresponding to proteolytic cleavage sites and mature endothelin-3 were 
analysed. By direct sequencing, three causative RET mutations were confirmed; a 
Phe to Ser substitution at codon 174, a Cys to Tyr substitution at codon 197, 
and a point mutation at the splice acceptor site of intron 12, in patients with 
aganglionosis confined to the rectosigmoid colon, the transverse colon, and the 
total colon, respectively. In the EDNRB locus, two mutations were observed; a 
nonsense mutation of Trp to stop at codon 275, and a T insertion at nucleotide 
878, in patients with aganglionosis confined to the rectosigmoid colon, and the 
descending colon, respectively. No mutation was detected in the EDN3 gene. 
Mutation rates were 7.3% in the RET and 5% in the EDNRB gene. Our data indicate 
that RET and EDNRB mutations have a role in the aetiology of some sporadically 
occurring HSCR. However, the low mutation rate of susceptibility genes in 
sporadically occurring HSCR suggests that other genes or environmental factors 
are involved in the development of the disease.