Close linkage with the RET proto-oncogene and boundaries of deletion mutations in autosamal dominant Hirschsprung disease

Tight linkage with the RET proto-oncogene (Zmax = 3.41 at theta = 0.00), analysis of recombinants and detection of a familial microdeletion in a large pedigree restrict the mapping of the Hirschsprung (HSCR) gene previously localized on proximal 10q. The molecular characterization of the familial microdeletion and of 3 additional cytogenetically visible de novo deletions, isolated in somatic cell hybrids, identify a smallest region of overlap of 250 Kb. This contains the RET proto-oncogene where missense mutations causing multiple endocrine neoplasia type 2A (MEN 2A) phenotype were recently found. The pentagastrin test (which detects preclinical forms of MEN 2A or B) is negative in adult HSCR patients with deletions of the RET gene. This represents a good candidate for the search of mutations causing HSCR.