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Interaction between a chromosome 10 RET enhancer and chromosome 21 in the Down syndrome–Hirschsprung disease association
Author(s) -
Arnold Stacey,
Pelet Anna,
Amiel Jeanne,
Borrego Salud,
Hofstra Robert,
Tam Paul,
Ceccherini Isabella,
Lyonnet Stanislas,
Sherman Stephanie,
Chakravarti Aravinda
Publication year - 2009
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.20944
Subject(s) - biology , genetics , allele , hirschsprung's disease , enhancer , chromosome , chromosome 21 , genetic association , disease , population , transmission disequilibrium test , chromosome 9 , gene , single nucleotide polymorphism , medicine , genotype , gene expression , haplotype , environmental health
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. Hum Mutat 30:1–5, 2009. © 2009 Wiley‐Liss, Inc.