The RET proto-oncogene, located at 10q11.2, encodes receptor tyrosine kinase expressed during neural crest development and is involved in different human neurocristopathies such as the multiple endocrine neoplasia type 2 (MEN 2) syndromes and Hirschsprung’s disease (HSCR).¹ HSCR (OMIM 142623), or aganglionic megacolon, is a common developmental disorder characterised by the absence of enteric neurones in variable lengths of the distal gastrointestinal tract, resulting in functional intestinal obstruction. Although RET is considered to be the major gene involved in HSCR, only a subset of HSCR patients can be attributable to traditional germline RET mutations (50% of familial HSCR and 10–15% of sporadic cases in selected series,^2,3 or 30% of familial and 3% of sporadic cases in a population based study⁴). In an even smaller subset of HSCR patients (5–10%), germline variants are present in other genes, generally related to the developmental programme of neural crest cells, such as the glial cell line derived neurotrophic factor (GDNF), neurturin (NTN), endothelin 3 (EDN3), endothelin receptor β (EDNRB), endothelin converting enzyme 1 (ECE1), transcriptional factors SOX10 and PHOX2B, and Smad interacting protein 1 (SIP1).^5–7 In addition, RET modifying gene loci at 9q31, 3p21, 10q11, and 19q12 have been described associated with an HSCR phenotype.^8,9 Because traditional germline mutations accounted for such a small subset of HSCR, we sought to determine whether there are more common susceptibility factors which predispose to a majority of HSCR cases. The silent variant A45A was described by our group in the only member from a MEN 2A/HSCR family co-segregating both phenotypes.¹⁰ When this variant in codon 45 (exon 2) and the RET haplotypes carrying it were found to be highly associated with a large subset of non-familial HSCR,^11,12 it prompted us to propose that this …