title: Interaction between a chromosome 10 RET enhancer and chromosome 21 in the Down syndrome-Hirschsprung disease association.
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+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.
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Stacey
authors.initials: S
authors.lastname: Arnold
authors.forename: Anna
authors.initials: A
authors.lastname: Pelet
authors.forename: Jeanne
authors.initials: J
authors.lastname: Amiel
authors.forename: Salud
authors.initials: S
authors.lastname: Borrego
authors.forename: Robert
authors.initials: R
authors.lastname: Hofstra
authors.forename: Paul
authors.initials: P
authors.lastname: Tam
authors.forename: Isabella
authors.initials: I
authors.lastname: Ceccherini
authors.forename: Stanislas
authors.initials: S
authors.lastname: Lyonnet
authors.forename: Stephanie
authors.initials: S
authors.lastname: Sherman
authors.forename: Aravinda
authors.initials: A
authors.lastname: Chakravarti
mesh_terms: D016022:Case-Control Studies; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics*; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics*; D004314:Down Syndrome / Q000150:complications* / Q000235:genetics; D004742:Enhancer Elements, Genetic; D006627:Hirschsprung Disease / Q000150:complications* / Q000235:genetics; D006801:Humans; D018895:Microsatellite Repeats / Q000235:genetics; D009630:Nondisjunction, Genetic; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*
chemical_list: D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human