Genome-wide profile of copy number variants for Hirschsprung disease

Abstract

Hirschsprung disease (HSCR, aganglionic megacolon) is a developmental disorder characterised by the absence of the enteric ganglia along the intestinal tract. In addition to the major implicating gene RET, common polymorphisms, rare mutations and chromosomal abnormalities have been found to be associated with HSCR. The most common associated chromosomal abnormality is trisomy 21 (Down syndrome). Other chromosomal aberrations including 13q chromosomal deletions were also reported, which pinpointed the region for the discovery of disesase susceptibility loci, such as EDNRB. To characterize the copy number variants for HSCR, we analyzed 139 HSCR patients and 333 controls previously genotyped by Affymetrix 500k SNP arrays using Birdsuite. For HSCR patients, we identified 92 duplications and 60 deletions of at least 100kb. The total burden for rare and singleton CNVs increased for cases when compared to controls, both for the number of CNVs per individual (p = 0.0008) and the number of overlapping genes (p < 0.0004). In particular, long singleton duplications and deletions were identified for HSCR patients. Focusing on highly confident structural variations revealed three duplications ranging from 1.8 to 10Mb, spanning 8p21, 15q11-13 and 16p12. Two nonoverlapping deletions (14.9 & 29.7Mb) with both breakpoints residing in 11q23 were also shown. As previously reported, a 16Mb deletion overlapping with EDNRB was found on one HSCR patient. Together with other shorter variants, this finding could account for a sustainable proportion of susceptibilty to HSCR.