Interaction between a chromosome 10 RET enhancer and chromosome 21 in the down syndrome-hirschsprung disease association

Stacey Arnold, Anna Pelet, Jeanne Amiel, Salud Borrego, Robert Hofstra, Paul Tam, Isabella Ceccherini, Stanislas Lyonnet, Stephanie Sherman, Aravinda Chakravarti

Research output: Contribution to journalArticle

Abstract

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 19.7 (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 RET19.7 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 RETand 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.

Original languageEnglish
Pages (from-to)771-775
Number of pages5
JournalHuman Mutation
Volume30
Issue number5
DOIs
Publication statusPublished - May 2009

Keywords

  • Complex disorder
  • Down syndrome
  • Gene dosage
  • Hirschsprung disease
  • RET

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Arnold, S., Pelet, A., Amiel, J., Borrego, S., Hofstra, R., Tam, P., Ceccherini, I., Lyonnet, S., Sherman, S., & Chakravarti, A. (2009). Interaction between a chromosome 10 RET enhancer and chromosome 21 in the down syndrome-hirschsprung disease association. Human Mutation, 30(5), 771-775. https://doi.org/10.1002/humu.20944