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Homozygosity for a frequent and weakly penetrant predisposing allele at the RET locus in sporadic Hirschsprung disease
  1. A Pelet1,
  2. L de Pontual1,
  3. M Clément-Ziza1,
  4. R Salomon1,
  5. C Mugnier1,
  6. F Matsuda2,
  7. M Lathrop2,
  8. A Munnich1,
  9. J Feingold1,
  10. S Lyonnet1,
  11. L Abel3,
  12. J Amiel1
  1. 1Unité de Recherches sur les Handicaps Génétiques de l’Enfant INSERM U-393 and Département de Génétique, Hôpital Necker-Enfants Malades, Paris, France
  2. 2Centre National de Génotypage, Evry, France
  3. 3Laboratoire de Génétique Humaine des Maladies Infectieuses, INSERM U-550, Hôpital Necker-Enfants Malades, University Paris 5 Medical School, Paris, France
  1. Correspondence to:
 Stanislas Lyonnet
 Département de Génétique, Hôpital Necker-Enfants Malades, 149, rue de Sèvres, 75743 Paris Cedex 15, France;

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Hirschsprung disease (HSCR), the most common malformation of the hindgut (1/5000 live births), is a single-field neural crest derived malformation characterised by the absence of enteric ganglia along a variable length of the intestine.1 The genetics of HSCR are complex, considering a skewed sex ratio in favour of females (1/4) and recurrence risk figures whose values depend on the length of the aganglionic segment as well as the gender of affected individuals (mean value of 4%, ranging from 1 to 30%).2,3 All genetic and functional evidence points to the RET proto-oncogene as the major disease causing locus in HSCR. In particular, almost all HSCR families co-segregate with markers of chromosome 10q11.2 where the RET gene locus has been mapped,4–6 although modifier genes are involved.7,8 Nonetheless, in most series worldwide, a mutation within the RET gene coding sequence can be detected in only 40% and 10–20% of familial and sporadic cases, respectively.9–11 These data led to speculation that a frequent hypomorphic allele(s) must exist at the RET locus. To address this question, several groups have used linkage disequilibrium mapping, mostly in case control studies,12–17 taking advantage of single nucleotide polymorphisms (SNPs) scattered along the vast genomic domain encompassing the RET locus (55 kb). These studies consistently indicated that a predisposing haplotype is located in the 5′ region of the RET gene, whatever the ethnic background, with some functional data favouring the role of promotor variants.18,19 In order to refine the mapping of predisposing allele(s) at the RET locus and to characterise its genetic behaviour, we used a transmission disequilibrium test (TDT) across the RET gene, in a series of HSCR cases divided according to family type (sporadic or multiplex) and the presence/absence of a RET gene mutation. We …

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  • This work was supported by European Union grants 2001-01646 and grants from GIS Maladies Rares INSERM-AFM.

  • Competing interests: none declared