Analysis of RET, ZEB2, EDN3 and GDNF genomic rearrangements in 80 patients with Hirschsprung disease (using multiplex ligation-dependent probe amplification).
Because the RET protooncogene, the major susceptibility gene for HD, also plays a role in normal kidney development and in the multiple endocrine neoplasia type 2 cancer syndrome, we analyzed our patient's constitutional DNA for mutations in RET commonly found in multiple endocrine neoplasia type 2A.
Although the ability to discern the impact of a mutation is imperfect, our analyses permit substantial discrimination between predicted functional classes of RET mutations and disease severity even for a multigenic disease such as Hirschsprung disease.
A founding locus within the RET proto-oncogene may account for a large proportion of apparently sporadic Hirschsprung disease and a subset of cases of sporadic medullary thyroid carcinoma.
Genetic linkage analysis in familial HSCR with both long- and short-segment phenotypes has demonstrated a tight linkage to the RET locus, while the phenotype within a HSCR family is characterised by an incomplete penetrance or a variable extension of the aganglionosis.
Loss-of-function germline mutations of the RET proto-oncogene are reported in familial and sporadic cases of Hirschsprung disease (HSCR) with a variable frequency.
The data on discrepancy between macroscopic and microscopic transitions may enable us to concentrate the sites of the leveling biopsy more accurately especially in cases of long type intestinal aganglionosis carrying RET gene mutation.
Statistically significant joint transmission of RET and EDNRB alleles in affected individuals and non-complementation of aganglionosis in mouse intercrosses between Ret null and the Ednrb hypomorphic piebald allele are suggestive of epistasis between EDNRB and RET.