Interaction between a chromosome 10 RET enhancer and chromosome 21 in the Down syndrome-Hirschsprung disease association

Hum Mutat. 2009 May;30(5):771-5. doi: 10.1002/humu.20944.


Individuals with Down syndrome (DS) display a 40-fold greater risk of Hirschsprung disease (HSCR) than the general population of newborns implicating chromosome 21 in HSCR etiology. Here we demonstrate that the RET enhancer polymorphism RET+9.7 (rs2435357:C>T) at chromosome 10q11.2 is associated with HSCR in DS individuals both by transmission disequilibrium (P=0.0015) and case-control (P=0.0115) analysis of matched cases. Interestingly, the RET+9.7 T allele frequency is significantly different between individuals with DS alone (0.26+/-0.04), HSCR alone (0.61+/-0.04), and those with HSCR and DS (0.41+/-0.04), demonstrating an association and interaction between RET and chromosome 21 gene dosage. This is the first report of a genetic interaction between a common functional variant (rs2435357) and a not infrequent copy number error (chromosome 21 dosage) in two human developmental disorders.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Case-Control Studies
  • Chromosomes, Human, Pair 10 / genetics*
  • Chromosomes, Human, Pair 21 / genetics*
  • Down Syndrome / complications*
  • Down Syndrome / genetics
  • Enhancer Elements, Genetic*
  • Hirschsprung Disease / complications*
  • Hirschsprung Disease / genetics
  • Humans
  • Microsatellite Repeats / genetics
  • Nondisjunction, Genetic
  • Polymorphism, Single Nucleotide / genetics
  • Proto-Oncogene Proteins c-ret / genetics*


  • Proto-Oncogene Proteins c-ret
  • RET protein, human