title: 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 = 1.50 × 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.
authors.affiliation: Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Clara Sze-Man
authors.initials: CS
authors.lastname: Tang
authors.forename: Guo
authors.initials: G
authors.lastname: Cheng
authors.forename: Man-Ting
authors.initials: MT
authors.lastname: So
authors.forename: Benjamin Hon-Kei
authors.initials: BH
authors.lastname: Yip
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Miao
authors.forename: Emily Hoi-Man
authors.initials: EH
authors.lastname: Wong
authors.forename: Elly Sau-Wai
authors.initials: ES
authors.lastname: Ngan
authors.forename: Vincent Chi-Hang
authors.initials: VC
authors.lastname: Lui
authors.forename: You-Qiang
authors.initials: YQ
authors.lastname: Song
authors.forename: Danny
authors.initials: D
authors.lastname: Chan
authors.forename: Kenneth
authors.initials: K
authors.lastname: Cheung
authors.forename: Zhen-Wei
authors.initials: ZW
authors.lastname: Yuan
authors.forename: Liu
authors.initials: L
authors.lastname: Lei
authors.forename: Patrick Ho-Yu
authors.initials: PH
authors.lastname: Chung
authors.forename: Xue-Lai
authors.initials: XL
authors.lastname: Liu
authors.forename: Kenneth Kak-Yuen
authors.initials: KK
authors.lastname: Wong
authors.forename: Christian R
authors.initials: CR
authors.lastname: Marshall
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scherer
authors.forename: Steve
authors.initials: S
authors.lastname: Scherer
authors.forename: Stacey S
authors.initials: SS
authors.lastname: Cherny
authors.forename: Pak-Chung
authors.initials: PC
authors.lastname: Sham
authors.forename: Paul Kwong-Hang
authors.initials: PK
authors.lastname: Tam
authors.forename: Maria-Mercè
authors.initials: MM
authors.lastname: Garcia-Barceló
mesh_terms: D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D005787:Gene Frequency; D055106:Genome-Wide Association Study; D005838:Genotype; D006239:Haplotypes; D006627:Hirschsprung Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D020880:Neuregulins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
chemical_list: C486357:NRG3 protein, human; D020880:Neuregulins