Gastrointestinal Tract: Molecular Genetics of Hirschsprung Disease


Hirschsprung disease is a complex, heterogeneous disorder, resulting from absence of the intramural intestinal ganglion cells (congenital intestinal aganglionosis) owing to failure of migration from the neural crest during embryonic development. Therefore, Hirschsprung disease is considered a neural crest disorder (neurocristopathy). Nine genes and three signal pathways have been identified in relation to the aetiology of this group of disorders. In addition, disease‐related noncoding regions in the RET gene contribute to the causes by interacting with at least one of the other predisposing genes. The disease susceptibility between males and females differs by a factor of 5 (5:1 higher disease frequency in males than in females).

Key Concepts:

  • Hirschsprung disease is currently the best understood multifactorial, nonMendelian genetic disorder.

  • Mutations in the receptor tyrosine kinase gene RET located at human chromosome 10q11.1 play a pivotal role in the etiology, in combination with other genes.

  • A common noncoding variant in intron 1 of the RET gene within a conserved enhancer‐like DNA sequence markedly influences the susceptibility to congenital intestinal aganglionosis.

  • This variant reduces enhancer activity in vitro and contributes to the disease risk 20‐fold more than other rare alleles, in spite of its low penetrance.

  • The eight other known genes involved in the genetic aetiology account for less than 30% of patients.

  • Three different signal pathways related to ganglion cell migration and intramural intestinal function are involved in the genetic pathogenesis of congenital intestinal aganglionosis: (1) the RET receptor kinase pathway with the RET gene and its ligand GDNF (glial cell line‐derived neurotrophic factor), (2) the endothelin type B receptor pathway with the EDNRB receptor and its ligand EDN3 (endothelin‐3) and (3) the transcription factor SOX10.

  • A single genetic change in any of the known genes and chromosomal regions predisposing to congenital intestinal aganglionosis is neither sufficient nor necessary to cause the disease.

  • The genetic effects differ in males and females. The frequency of transmission of predisposing factors differs between males and females, resulting in a 5.7‐fold and 2.1‐fold increase in susceptibility in males and females, respectively.

  • The predisposing RET susceptibility allele differs in world‐like frequency. It is virtually absent in Africa (less than 5%) in contrast to Asia (40% in China and Japan) and Europe (25%).

  • In about 12% of patients, congenital intestinal aganglionosis occurs in syndromic form associated with other clinical manifestations outside the GI tract, usually in a monogenetic inheritance pattern.

Keywords: gastrointestinal disorders; embryology of the GI tract; Hirschsprung disease; aganglionosis; multigenic inheritance; intestinal aganglionosis; RET; SOX10; noncoding variant; genetic susceptibility; penetrance

Figure 1.

Abdominal distension owing to megacolon in a child (a) and in an infant (b). Photograph in (b) courtesy of Dr. Lester Martin, Cincinnati (1965) figure from Passarge and Bruder, .

Figure 2.

Functional domains of the RET Receptor Tyrosine Kinase in relation to types of mutations (MEN). The numbers indicate amino acid positions along the RET protein.



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Web Links

EDN3 (endothelin 3); LocusID: 1908. LocusLink:

EDN3 (endothelin 3); MIM number: 131242. OMIM:‐post/Omim/dispmim?131242

EDNRB (endothelin receptor type B); LocusID: 1910. LocusLink:

EDNRB (endothelin receptor type B); MIM number: 131244. OMIM:‐post/Omim/dispmim?131244

GDNF (glial cell derived neurotrophic factor); LocusID: 2668. LocusLink:

GDNF (glial cell derived neurotrophic factor); MIM number: 600837. OMIM:‐post/Omim/dispmim?600837

OMIM (Online Mendelian Inheritance in Man).

RET (ret proto‐oncogene (multiple endocrine neoplasia and medullary thyroid carcinoma 1, Hirschsprung disease)); LocusID: 5979. LocusLink:

RET (ret proto‐oncogene (multiple endocrine neoplasia and medullary thyroid carcinoma 1, Hirschsprung disease)); MIM number: 164761. OMIM:‐post/Omim/dispmim?164761

SOX10 (SRY (sex determining region Y)‐box 10); LocusID: 6663. LocusLink:

SOX10 (SRY (sex determining region Y)‐box 10); MIM number: 602229. OMIM:‐post/Omim/dispmim?602229

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Passarge, Eberhard(Jun 2011) Gastrointestinal Tract: Molecular Genetics of Hirschsprung Disease. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0005518.pub2]