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  • Single nucleotide polymorphic alleles in the 5′ region of the RET proto-oncogene define a risk haplotype in Hirschsprung’s disease

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Single nucleotide polymorphic alleles in the 5′ region of the RET proto-oncogene define a risk haplotype in Hirschsprung’s disease
  1. M Sancandi1,
  2. P Griseri1,
  3. B Pesce1,
  4. G Patrone1,
  5. F Puppo1,
  6. M Lerone1,
  7. G Martucciello2,
  8. G Romeo4,
  9. R Ravazzolo3,
  10. M Devoto5,
  11. I Ceccherini1
  1. 1Laboratorio di Genetica Molecolare, Istituto G Gaslini, Genova, Italy
  2. 2Divisione e Cattedra di Chirurgia Pediatrica, Istituto G Gaslini, Genova, Italy
  3. 3Laboratories di Genetica Moleculare, Istituto G Gaslini, Genova, Italy
  4. 4Cattedra di Genetica Medica, Università di Bologna, Bologna, Italy
  5. 5Department of Research, Nemours Children’s Clinic, Wilmington, Delaware, USA
  1. Correspondence to:
 Isabella Ceccherini, Laboratorio di Genetica Molecolare, Istituto Giannina Gaslini, L.go G Gaslini 5, 16148 Genova, Italy;
 isa.c{at}unige.it

https://doi.org/10.1136/jmg.40.9.714

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    Hirschsprung’s disease is a congenital disorder characterised by intestinal obstruction caused by the absence of parasympathetic intrinsic ganglion cells along variable lengths of the colon.1 The high proportion of sporadic cases (80–90%), the variable expressivity, the incomplete sex dependent penetrance, and the involvement of several genes, most of which are yet to be identified, show a complex pattern of inheritance for this disorder.2–4 The RET proto-oncogene is the major gene involved in Hirschsprung’s disease, accounting for a high proportion of both familial (about 50%) and sporadic cases (10–15%). Five to ten per cent of patients show alterations in other genes such as the glial cell line derived neurotrophic factor (GDNF), neurturin (NTN), endothelin 3 (EDN3), endothelin B receptor (EDNRB), endothelin converting enzyme 1 (ECE1), transcriptional factor SOX10, and Smad interacting protein 1 (SIP1).1,5 The small number of affected patients with known mutations confirms the involvement of modifier genes or additional genetic risk factors, some of which are already mapped,3,4,6 in the aetiology of the disease.

    According to what was expected for a complex inheritance pattern, several common polymorphisms of the RET proto-oncogene have been associated with a variable risk of developing Hirschsprung’s disease. Moreover, specific RET haplotypes have been found to have either protective or predisposing effects, or to modulate the severity of the resulting phenotype.6–12 In particular, specific haplotypes comprising the rarer allele of a single nucleotide polymorphism (SNP) of exon 2 (A45A) have been strongly associated with Hirschsprung’s disease, whereas the haplotype including the rarer allele of exon 14 SNP (S836S) has shown a low penetrant protective effect against the disease.11,12 Recently, Borrego et al have extended the genetic analysis of the SNP2 associated predisposing haplotype for Hirschsprung’s disease, hypothesising the existence of a …

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