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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, CSM3 3
Cheng, G3
So, MT3
Yip, BHK3 3
Miao, XP3 5
Wong, EHM3
Ngan, ESW3 3
Lui, VCH3 3
Song, YQ3
Chan, D3
Cheung, K3
Yuan, ZW4
Lei, L1
Chung, PHY3
Liu, XL3
Wong, KKY3
Marshall, CR2
Scherer, S2 6
Cherny, SS3 3 3
Sham, PC3 3 3 3
Tam, PKH3
GarciaBarceló, MM3 3
 
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
2012 SCImago Journal Rankings: 5.375
 
DOIhttp://dx.doi.org/10.1371/journal.pgen.1002687
 
PubMed Central IDPMC3349728
 
ISI Accession Number IDWOS: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.

 
ReferencesReferences in Scopus
 
GrantsIdentification of functional variants in Neuregulin-1 (NRG1), a newly discovered Hirschsprungs disease gene
Genetic dissection of Hirschsprung's disease
Developmental genomics and skeletal research
 
DC FieldValue
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.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.eissn1553-7404
 
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
2012 SCImago Journal Rankings: 5.375
 
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.projectIdentification of functional variants in Neuregulin-1 (NRG1), a newly discovered Hirschsprungs disease gene
 
dc.relation.projectGenetic dissection of Hirschsprung's disease
 
dc.relation.projectDevelopmental genomics and skeletal research
 
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
 
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Author Affiliations
  1. Shenzhen Children's Hospital
  2. The Centre for Applied Genomics University of Toronto
  3. The University of Hong Kong Li Ka Shing Faculty of Medicine
  4. China Medical University Shenyang
  5. Huazhong University of Science and Technology
  6. University of Toronto