LONG-SEGMENT AND SHORT SEGMENT FAMILIAL HIRSCHSPRUNGS-DISEASE - VARIABLE CLINICAL EXPRESSION AT THE RET LOCUS

Hirschsprung's disease (aganglionic megacolon, HSCR) is a frequent con dition of unknown origin (1/5000 live births) resulting in intestinal obstruction in neonates and severe constipation in infants and adults. In the majority of cases (80%), the aganglionic tract involves the re ctum and the sigmoid colon only (short segment HSCR), while in 20% of cases it extends toward the proximal end of the colon (long segment HS CR). In a previous study, we mapped a gene for long segment familial H SCR to the proximal long arm of chromosome 10 (10q11.2). Further linka ge analyses in familial HSCR have suggested tight linkage of the disea se gene to the RET protooncogene mapped to chromosome 10q11.2. Recentl y, nonsense and missense mutations of RET have been identified in HSCR patients. However, the question of whether mutations of the RET gene account for both long segment and short segment familial HSCR remained unanswered. We have performed genetic linkage analyses in 11 long seg ment HSCR families and eight short segment HSCR families using microsa tellite DNA markers of chromosome 10q. In both anatomical forms, tight pairwise linkage with no recombinant events was observed between the RET proto-oncogene locus and the disease locus (Zmax = 2.16 and Zmax=5 .38 for short segment and long segment HSCR respectively at 0=0%). Mul tipoint linkage analyses performed in the two groups showed that the m aximum likelihood estimate was at the RET locus. Moreover, we show tha t point mutations of the RET proto-oncogene occur either in long segme nt or in short segment HSCR families and we provide evidence for incom plete penetrance of the disease causing mutation. These data suggest t hat the two anatomical forms of familial HSCR, which have been separat ed on the basis of clinical and genetic criteria, may be regarded as t he variable clinical expression of mutations at the RET locus.