DIVERSITY OF RET PROTOONCOGENE MUTATIONS IN FAMILIAL AND SPORADIC HIRSCHSPRUNG DISEASE

Hirschsprung disease (HSCR) is a common congenital malformation (1 in 5 000 live births) due to the absence of autonomic ganglia in the term inal hindgut, and resulting in intestinal obstruction in neonates, Rec ently, a dominant gene for familial HSCR has been mapped to chromosome sub-band 10q11.2 and the disease has been ascribed to mutations in a tyrosine kinase receptor gene mapping to this region, the RET proto-on cogene, Studying the 20 exons of the RET gene by a combination of dena turating gradient gel electrophoresis and single strand conformation p olymorphism in a large series of HSCR patients (45 sporadic cases and 35 familial forms), we found mutations of the RET gene in 50% of famil ial HSCR, regardless of the length of the aganglionic segment, The mea n penetrance of the mutant allele in familial HSCR was significantly h igher in males (72%) than in females (51%), Most interestingly, mutati ons at the RET locus accounted for at least 1/3 of sporadic HSCR in ou r series, These mutations were scattered along the length of the gene, Finally, among the mutations identified in sporadic cases (16/45), se ven proved to be de novo mutations suggesting that new mutations at th e RET locus significantly contribute to sporadic HSCR, Taken together, the low penetrance of the mutant gene, the lack of genotype-phenotype correlation, the sex-dependent effect of RET mutations and the variab le clinical expression of the disease support the existence of one or more modifier genes in familial HSCR.