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A novel susceptibility locus for Hirschsprung’s disease maps to 4q31.3–q32.3
  1. A S Brooks1,
  2. P A Leegwater1,
  3. G M Burzynski3,
  4. P J Willems4,
  5. B de Graaf1,
  6. I van Langen5,
  7. P Heutink6,
  8. B A Oostra1,
  9. R M W Hofstra3,
  10. A M Bertoli-Avella1
  1. 1Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands
  2. 2Department of Clinical Sciences of Companion Animals, University of Utrecht, The Netherlands
  3. 3Department of Medical Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
  4. 4GENDIA, Antwerp, Belgium
  5. 5Department of Medical Genetics, Academic Medical Center, Amsterdam, The Netherlands
  6. 6Section of Medical Genomics, Department of Human Genetics and Department of Biological Psychology, VU University Medical Center, Amsterdam, The Netherlands
  1. Correspondence to:
 Dr A S Brooks
 Department of Clinical Genetics, Erasmus MC, Westzeedijk 112, 3016 AH Rotterdam, the Netherlands; a.brooks{at}


We report on a multigenerational family with isolated Hirschsprung’s disease (HSCR). Five patients were affected by either short segment or long segment HSCR. The family consists of two main branches: one with four patients (three siblings and one maternal uncle) and one with one patient. Analysis of the RET gene, the major gene involved in HSCR susceptibility, revealed neither linkage nor mutations. A genome wide linkage analysis was performed, revealing suggestive linkage to a region on 4q31–q32 with a maximum parametric multipoint LOD score of 2.7. Furthermore, non-parametric linkage (NPL) analysis of the genome wide scan data revealed a NPL score of 2.54 (p = 0.003) for the same region on chromosome 4q (D4S413–D4S3351). The minimum linkage interval spans a region of 11.7 cM (12.2 Mb). No genes within this chromosomal interval have previously been implicated in HSCR. Considering the low penetrance of disease in this family, the 4q locus may be necessary but not sufficient to cause HSCR in the absence of modifying loci elsewhere in the genome. Our results suggest the existence of a new susceptibility locus for HSCR at 4q31.3-q32.3.

  • HSCR, Hirschsprung’s disease
  • LS-HSCR, long segment Hirschsprung’s disease
  • NPL, non-parametric linkage
  • SNP, single nucleotide polymorphism
  • SS-HSCR, short segment Hirschsprung’s disease
  • STRP, short tandem repeat polymorphism
  • Hirschsprung’s disease
  • RET
  • 4q31.3–q32.3

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  • The first two authors contributed equally to this work.

  • Competing interests: there are no competing interests