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

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=1.50x10-5), particularly for those encompassing genes (p=5.00x10-6). We identified 246 rare-genic CNVs exclusive to patients. Among those, we detected a NRG3 deletion (p=1.64x10-3). Subsequent NRG3 follow-up (96 additional patients and 105 controls) revealed 9 deletions and 2 de novo duplications among patients and two deletions among controls (p=1.67x10-6). 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=1.50x10-5), non-syndromic patients were enriched in CNV number when compared to controls (p=4.00x10-6) 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.