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Investigation of germline GFRA4 mutations and evaluation of the involvement of GFRA1, GFRA2, GFRA3, and GFRA4 sequence variants in Hirschsprung disease

The RET proto-oncogene on 10q11.2, which encodes a receptor tyrosine kinase expressed in neural crest and its derivatives, is the susceptibility gene for multiple endocrine neoplasia type 2 (MEN 2), characterised by medullary thyroid carcinoma, phaeochromocytoma, and hyperparathyroidism, and one of several susceptibility genes for Hirschsprung disease (HSCR).1–4 HSCR is characterised by aganglionosis of the gut resulting from inappropriate and premature apoptosis of the enteric ganglia. Initially, it was believed that approximately 50% of familial HSCR and 30% of isolated HSCR were the result of germline loss of function mutations in the RET proto-oncogene5,6 (reviewed by Eng and Mulligan7). However, these data were obtained with highly selected series of families and patients with HSCR. A population based survey of HSCR cases showed that only 3% of isolated HSCR carried traditional germline RET mutations.8 In the context of these data and the anecdotal observation that a RET codon 45 variant seemed to modify the expression of HSCR in a MEN 2/HSCR family with RET codon 618 mutation,9 we began to examine the polymorphic alleles at codon 45 and the other coding variants as common low penetrance alleles for HSCR susceptibility. Indeed, we found that certain haplotypes or pairs of haplotypes (“genotypes”) comprising specific combinations of RET polymorphic sequence variants were highly associated with isolated HSCR.9–11 These observations were also noted among HSCR populations from elsewhere in the world.12–14 These data implied that RET and/or loci in proximity to it could act as common low penetrance alleles which predisposed to isolated HSCR.

There are perhaps seven susceptibility genes for syndromic and non-syndromic HSCR.3,415–25 Among these seven genes, RET is considered a major susceptibility gene for HSCR. RET is an unusual receptor tyrosine kinase in that it requires …