The Contributions of RET Noncoding Variation to Hirschsprung Disease

  • Zachary E. Stine
  • Andrew S. McCallionEmail author


First described by Danish pediatrician Harald Hirschsprung, Hirschsprung disease (HSCR) is a disorder of the enteric nervous system characterized by the absence of variable length of the submucous (Meissner’s) and myenteric (Auerbach’s) plexuses in the distal gut. As a defect in neural crest-derived cell population, Hirschsprung disease is considered a neurocristopathy. While HSCR was originally observed in sporadic cases, the advent of lifesaving surgical intervention has also given rise to the observation of familial forms of HSCR. Subsequently, its presentation in familial, sporadic, and syndromic form illuminated the genetics of HSCR. As this work has progressed the ret proto-oncogene (RET), a receptor tyrosine kinase has emerged as a central player in the development of HSCR, most frequently modified in effect by the contributions of risk alleles at other loci. This has been exemplified by the recent characterization of risk variants in a noncoding RET regulatory element, establishing it as a model for the study of multigenic disorders.


RET Hirschsprung Enhancer Enteric nervous system Cis-regulatory element Transcriptional regulation Disease NRG1 SOX10 Neural crest 



Bardet-Biedl syndrome


Congenital anomalies of the kidney and urinary tract


Central congenital hypoventilation syndrome


Enteric nervous system


Hirschsprung disease


Long-segment Hirschsprung disease


Multispecies conserved sequence


Multiple endocrine neoplasia type 2


Neural crest


ret proto-oncogene


Short-segment or classical Hirschsprung


Single-nucleotide polymorphism


Waardenburg-Shah type 4


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© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.McKusick – Nathans Institute of Genetic MedicineJohns Hopkins University School of MedicineBaltimoreUSA
  2. 2.Department of Molecular and Comparative PathobiologyJohns Hopkins University School of MedicineBaltimoreUSA

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