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.

Figure 1

Chromosomal and genetic locations of microsatellite markers. The deCODE sex-equal genetic map of human chromosome 21 (male length 47.31cM, female length 76.40 cM, sex-equal length 61.86 cM¹⁴) is shown on the right, and microsatellite marker positions are extrapolated to their locations on the cytogenetic map in the center by solid or dashed lines. Only the microsatellite markers used in this study, spanning the entire long arm, are named: these and the remaining deCODE markers are represented by hashes along the length of the genetic map, and they are connected to the cytogenetic map by solid lines; two additional markers were genotyped and their positions, interpolated on the genetic map (based on the chromosome 21 DNA sequence), are represented by diamonds and connected to the cytogenetic map by dashed lines. Nine genes that are differentially expressed in mice with an HSCR phenotype⁹ are shown on the cytogenetic map (red text and lines)^14,15.

Figure 2

Nondisjunction map for matched DS and DS+HSCR trios. The relative positions of microsatellite markers (numbered as in parentheses in Figure 1), SOD1 and TFF3 are indicated along the q arm of Chromosome 21 (top). Below, the analogous region of Chr 21 is represented for each proband, with definitive calls of reduction represented by yellow boxes and definitive calls of nonreduction represented by blue boxes for all relevant loci. Probands are further grouped according to the mode of inheritance (“with recombination” is abbreviated to w/recomb.) and phenotype.