Genome-wide copy number analysis uncovers a new HSCR gene: NRG3

PLoS Genet. 2012;8(5):e1002687. doi: 10.1371/journal.pgen.1002687. Epub 2012 May 10.

Abstract

Hirschsprung disease (HSCR) is a congenital disorder characterized by aganglionosis of the distal intestine. To assess the contribution of copy number variants (CNVs) to HSCR, we analysed the data generated from our previous genome-wide association study on HSCR patients, whereby we identified NRG1 as a new HSCR susceptibility locus. Analysis of 129 Chinese patients and 331 ethnically matched controls showed that HSCR patients have a greater burden of rare CNVs (p = 1.50 × 10(-5)), particularly for those encompassing genes (p = 5.00 × 10(-6)). Our study identified 246 rare-genic CNVs exclusive to patients. Among those, we detected a NRG3 deletion (p = 1.64 × 10(-3)). Subsequent follow-up (96 additional patients and 220 controls) on NRG3 revealed 9 deletions (combined p = 3.36 × 10(-5)) and 2 de novo duplications among patients and two deletions among controls. Importantly, NRG3 is a paralog of NRG1. Stratification of patients by presence/absence of HSCR-associated syndromes showed that while syndromic-HSCR patients carried significantly longer CNVs than the non-syndromic or controls (p = 1.50 × 10(-5)), non-syndromic patients were enriched in CNV number when compared to controls (p = 4.00 × 10(-6)) or the syndromic counterpart. Our results suggest a role for NRG3 in HSCR etiology and provide insights into the relative contribution of structural variants in both syndromic and non-syndromic HSCR. This would be the first genome-wide catalog of copy number variants identified in HSCR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA Copy Number Variations / genetics*
  • Female
  • Gene Deletion*
  • Gene Frequency
  • Genome-Wide Association Study
  • Genotype
  • Haplotypes
  • Hirschsprung Disease / genetics*
  • Humans
  • Male
  • Neuregulins / genetics*
  • Polymorphism, Single Nucleotide

Substances

  • NRG3 protein, human
  • Neuregulins