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Gene Regulatory Sequences and Human Disease pp 169–194Cite as

The Contributions of RET Noncoding Variation to Hirschsprung Disease

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Abstract

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.

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Abbreviations

BBS:

Bardet-Biedl syndrome

CAKUT:

Congenital anomalies of the kidney and urinary tract

CCHS:

Central congenital hypoventilation syndrome

ENS:

Enteric nervous system

HSCR:

Hirschsprung disease

L-HSCR:

Long-segment Hirschsprung disease

MCS:

Multispecies conserved sequence

MEN2:

Multiple endocrine neoplasia type 2

NC:

Neural crest

RET:

ret proto-oncogene

S-HSCR:

Short-segment or classical Hirschsprung

SNP:

Single-nucleotide polymorphism

WS4:

Waardenburg-Shah type 4

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  1. McKusick – Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, 733 N. Broadway, BRB Suite 407, Baltimore, MD, 21205, USA

    Zachary E. Stine

  2. Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Andrew S. McCallion

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    Nadav Ahituv

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Stine, Z.E., McCallion, A.S. (2012). The Contributions of RET Noncoding Variation to Hirschsprung Disease. In: Ahituv, N. (eds) Gene Regulatory Sequences and Human Disease. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-1683-8_9

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