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

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TitleGenome-wide copy number analysis uncovers a new HSCR gene: NRG3
AuthorsTang, CSM1
Cheng, G1
So, MT1
Yip, BHK1
Miao, XP1 5
Wong, EHM1
Ngan, ESW1
Lui, VCH1
Song, YQ1
Chan, D1
Cheung, K1
Yuan, ZW4
Lei, L3
Chung, PHY1
Liu, XL1
Wong, KKY1
Marshall, CR2
Scherer, S2 6
Cherny, SS1
Sham, PC1
Tam, PKH1
GarciaBarceló, MM1
KeywordsCopy number variation
Gene deletion
Gene duplication
Gene expression regulation
Gene frequency
Issue Date2012
PublisherPublic Library of Science. The Journal's web site is located at http://www.plosgenetics.org/
CitationPlos Genetics, 2012, v. 8 n. 5 [How to Cite?]
DOI: http://dx.doi.org/10.1371/journal.pgen.1002687
AbstractHirschsprung 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. © 2012 Tang et al.
ISSN1553-7390
2011 Impact Factor: 8.694
2011 SCImago Journal Rankings: 1.813
DOIhttp://dx.doi.org/10.1371/journal.pgen.1002687
PubMed Central IDPMC3349728
ReferencesReferences in Scopus
GrantsExon sequencing of Semaphorin, a novel Hirschsprung's Disease susceptibility locus
Identification of functional variants in Neuregulin-1 (NRG1), a newly discovered Hirschsprungs disease gene
Genetic dissection of Hirschsprung's disease
Functional characterization of the V226L, H347Y, and P356L NRG1 mutations identified in Hirschsprung's disease patients
Sequencing of the neuregulin-1 (NRG1) gene in Hisrchprung's disease patients
Developmental genomics and skeletal research
DC Field
Value
dc.contributor.authorTang, CSM
dc.contributor.authorCheng, G
dc.contributor.authorSo, MT
dc.contributor.authorYip, BHK
dc.contributor.authorMiao, XP
dc.contributor.authorWong, EHM
dc.contributor.authorNgan, ESW
dc.contributor.authorLui, VCH
dc.contributor.authorSong, YQ
dc.contributor.authorChan, D
dc.contributor.authorCheung, K
dc.contributor.authorYuan, ZW
dc.contributor.authorLei, L
dc.contributor.authorChung, PHY
dc.contributor.authorLiu, XL
dc.contributor.authorWong, KKY
dc.contributor.authorMarshall, CR
dc.contributor.authorScherer, S
dc.contributor.authorCherny, SS
dc.contributor.authorSham, PC
dc.contributor.authorTam, PKH
dc.contributor.authorGarciaBarceló, MM
dc.date.accessioned2012-06-22T06:19:38Z
dc.date.available2012-06-22T06:19:38Z
dc.date.issued2012
dc.description.abstractHirschsprung 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. © 2012 Tang et al.
dc.description.grantExon sequencing of Semaphorin, a novel Hirschsprung's Disease susceptibility locus
dc.description.grantIdentification of functional variants in Neuregulin-1 (NRG1), a newly discovered Hirschsprungs disease gene
dc.description.grantGenetic dissection of Hirschsprung's disease
dc.description.grantFunctional characterization of the V226L, H347Y, and P356L NRG1 mutations identified in Hirschsprung's disease patients
dc.description.grantSequencing of the neuregulin-1 (NRG1) gene in Hisrchprung's disease patients
dc.description.grantDevelopmental genomics and skeletal research
dc.description.grantcode101808
dc.description.grantcode100485
dc.description.grantcode96945
dc.description.grantcode101813
dc.description.grantcode99882
dc.description.grantcode44444
dc.description.naturepublished_or_final_version
dc.identifier.citationPlos Genetics, 2012, v. 8 n. 5 [How to Cite?]
DOI: http://dx.doi.org/10.1371/journal.pgen.1002687
dc.identifier.doihttp://dx.doi.org/10.1371/journal.pgen.1002687
dc.identifier.hkuros200158
dc.identifier.isiWOS:000304864000018
Funding AgencyGrant Number
Hong Kong Research Grants CouncilHKU 775907M
HKU 765609M
Seed Funding Programme for Basic Research200910159040
200811159006
200911159190
University Grants Committee of Hong KongAoE/M-04/04
AOSPINEAOSBRC-07-02
Funding Information:

This work was supported by the Hong Kong Research Grants Council (HKU 775907M to PK-HT and HKU 765609M to M-MG-B) and by the Seed Funding Programme for Basic Research (200910159040 and 200811159006 to M-MG-B and 200911159190 to SSC). Support was also received from the University Grants Committee of Hong Kong (AoE/M-04/04) and AOSPINE (AOSBRC-07-02 to DC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

dc.identifier.issn1553-7390
2011 Impact Factor: 8.694
2011 SCImago Journal Rankings: 1.813
dc.identifier.issue5
dc.identifier.openurl
dc.identifier.pmcidPMC3349728
dc.identifier.pmid22589734
dc.identifier.scopuseid_2-s2.0-84863680217
dc.identifier.urihttp://hdl.handle.net/10722/149062
dc.identifier.volume8
dc.languageeng
dc.publisherPublic Library of Science. The Journal's web site is located at http://www.plosgenetics.org/
dc.publisher.placeUnited States
dc.relation.ispartofPLoS Genetics
dc.relation.referencesReferences in Scopus
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License
dc.subjectCopy number variation
dc.subjectGene deletion
dc.subjectGene duplication
dc.subjectGene expression regulation
dc.subjectGene frequency
dc.titleGenome-wide copy number analysis uncovers a new HSCR gene: NRG3
dc.typeArticle
Author Affiliations
  1. The University of Hong Kong Li Ka Shing Faculty of Medicine
  2. Hospital for Sick Children, The Centre for Applied Genomics, Toronto
  3. Shenzhen Children's Hospital
  4. China Medical University Shenyang
  5. Huazhong University of Science and Technology
  6. University of Toronto