Contribution of copy-number variation to Down syndrome-associated atrioventricular septal defects

Dhanya Ramachandran, Jennifer G. Mulle, Adam E. Locke, Lora J H Bean, Tracie C. Rosser, Promita Bose, Kenneth J. Dooley, Clifford L. Cua, George T Capone, Roger H Reeves, Cheryl L. Maslen, David J. Cutler, Stephanie L. Sherman, Michael E. Zwick

Research output: Contribution to journalArticle

Abstract

Purpose:The goal of this study was to identify the contribution of large copy-number variants to Down syndrome-associated atrioventricular septal defects, the risk for which in the trisomic population is 2,000-fold more as compared with that of the general disomic population.Methods:Genome-wide copy-number variant analysis was performed on 452 individuals with Down syndrome (210 cases with complete atrioventricular septal defects; 242 controls with structurally normal hearts) using Affymetrix SNP 6.0 arrays, making this the largest heart study conducted to date on a trisomic background.Results:Large, common copy-number variants with substantial effect sizes (OR > 2.0) do not account for the increased risk observed in Down syndrome-associated atrioventricular septal defects. By contrast, cases had a greater burden of large, rare deletions (P <0.01) and intersected more genes (P <0.007) as compared with controls. We also observed a suggestive enrichment of deletions intersecting ciliome genes in cases as compared with controls.Conclusion:Our data provide strong evidence that large, rare deletions increase the risk of Down syndrome-associated atrioventricular septal defects, whereas large, common copy-number variants do not appear to increase the risk of Down syndrome-associated atrioventricular septal defects. The genetic architecture of atrioventricular septal defects is complex and multifactorial in nature.Genet Med 17 7, 554-560.

Original languageEnglish (US)
Pages (from-to)554-560
Number of pages7
JournalGenetics in Medicine
Volume17
Issue number7
DOIs
StatePublished - Jul 2 2015

Fingerprint

Down Syndrome
Viverridae
Population
Genes
Single Nucleotide Polymorphism
Atrioventricular Septal Defect
Genome

Keywords

  • atrioventricular septal defects
  • ciliome
  • congenital heart defect
  • copy-number variation
  • Down syndrome

ASJC Scopus subject areas

  • Genetics(clinical)

Cite this

Ramachandran, D., Mulle, J. G., Locke, A. E., Bean, L. J. H., Rosser, T. C., Bose, P., ... Zwick, M. E. (2015). Contribution of copy-number variation to Down syndrome-associated atrioventricular septal defects. Genetics in Medicine, 17(7), 554-560. https://doi.org/10.1038/gim.2014.144

Contribution of copy-number variation to Down syndrome-associated atrioventricular septal defects. / Ramachandran, Dhanya; Mulle, Jennifer G.; Locke, Adam E.; Bean, Lora J H; Rosser, Tracie C.; Bose, Promita; Dooley, Kenneth J.; Cua, Clifford L.; Capone, George T; Reeves, Roger H; Maslen, Cheryl L.; Cutler, David J.; Sherman, Stephanie L.; Zwick, Michael E.

In: Genetics in Medicine, Vol. 17, No. 7, 02.07.2015, p. 554-560.

Research output: Contribution to journalArticle

Ramachandran, D, Mulle, JG, Locke, AE, Bean, LJH, Rosser, TC, Bose, P, Dooley, KJ, Cua, CL, Capone, GT, Reeves, RH, Maslen, CL, Cutler, DJ, Sherman, SL & Zwick, ME 2015, 'Contribution of copy-number variation to Down syndrome-associated atrioventricular septal defects', Genetics in Medicine, vol. 17, no. 7, pp. 554-560. https://doi.org/10.1038/gim.2014.144
Ramachandran, Dhanya ; Mulle, Jennifer G. ; Locke, Adam E. ; Bean, Lora J H ; Rosser, Tracie C. ; Bose, Promita ; Dooley, Kenneth J. ; Cua, Clifford L. ; Capone, George T ; Reeves, Roger H ; Maslen, Cheryl L. ; Cutler, David J. ; Sherman, Stephanie L. ; Zwick, Michael E. / Contribution of copy-number variation to Down syndrome-associated atrioventricular septal defects. In: Genetics in Medicine. 2015 ; Vol. 17, No. 7. pp. 554-560.
@article{68863c383d6348dfbda3ba8073ebc944,
title = "Contribution of copy-number variation to Down syndrome-associated atrioventricular septal defects",
abstract = "Purpose:The goal of this study was to identify the contribution of large copy-number variants to Down syndrome-associated atrioventricular septal defects, the risk for which in the trisomic population is 2,000-fold more as compared with that of the general disomic population.Methods:Genome-wide copy-number variant analysis was performed on 452 individuals with Down syndrome (210 cases with complete atrioventricular septal defects; 242 controls with structurally normal hearts) using Affymetrix SNP 6.0 arrays, making this the largest heart study conducted to date on a trisomic background.Results:Large, common copy-number variants with substantial effect sizes (OR > 2.0) do not account for the increased risk observed in Down syndrome-associated atrioventricular septal defects. By contrast, cases had a greater burden of large, rare deletions (P <0.01) and intersected more genes (P <0.007) as compared with controls. We also observed a suggestive enrichment of deletions intersecting ciliome genes in cases as compared with controls.Conclusion:Our data provide strong evidence that large, rare deletions increase the risk of Down syndrome-associated atrioventricular septal defects, whereas large, common copy-number variants do not appear to increase the risk of Down syndrome-associated atrioventricular septal defects. The genetic architecture of atrioventricular septal defects is complex and multifactorial in nature.Genet Med 17 7, 554-560.",
keywords = "atrioventricular septal defects, ciliome, congenital heart defect, copy-number variation, Down syndrome",
author = "Dhanya Ramachandran and Mulle, {Jennifer G.} and Locke, {Adam E.} and Bean, {Lora J H} and Rosser, {Tracie C.} and Promita Bose and Dooley, {Kenneth J.} and Cua, {Clifford L.} and Capone, {George T} and Reeves, {Roger H} and Maslen, {Cheryl L.} and Cutler, {David J.} and Sherman, {Stephanie L.} and Zwick, {Michael E.}",
year = "2015",
month = "7",
day = "2",
doi = "10.1038/gim.2014.144",
language = "English (US)",
volume = "17",
pages = "554--560",
journal = "Genetics in Medicine",
issn = "1098-3600",
publisher = "Lippincott Williams and Wilkins",
number = "7",

}

TY - JOUR

T1 - Contribution of copy-number variation to Down syndrome-associated atrioventricular septal defects

AU - Ramachandran, Dhanya

AU - Mulle, Jennifer G.

AU - Locke, Adam E.

AU - Bean, Lora J H

AU - Rosser, Tracie C.

AU - Bose, Promita

AU - Dooley, Kenneth J.

AU - Cua, Clifford L.

AU - Capone, George T

AU - Reeves, Roger H

AU - Maslen, Cheryl L.

AU - Cutler, David J.

AU - Sherman, Stephanie L.

AU - Zwick, Michael E.

PY - 2015/7/2

Y1 - 2015/7/2

N2 - Purpose:The goal of this study was to identify the contribution of large copy-number variants to Down syndrome-associated atrioventricular septal defects, the risk for which in the trisomic population is 2,000-fold more as compared with that of the general disomic population.Methods:Genome-wide copy-number variant analysis was performed on 452 individuals with Down syndrome (210 cases with complete atrioventricular septal defects; 242 controls with structurally normal hearts) using Affymetrix SNP 6.0 arrays, making this the largest heart study conducted to date on a trisomic background.Results:Large, common copy-number variants with substantial effect sizes (OR > 2.0) do not account for the increased risk observed in Down syndrome-associated atrioventricular septal defects. By contrast, cases had a greater burden of large, rare deletions (P <0.01) and intersected more genes (P <0.007) as compared with controls. We also observed a suggestive enrichment of deletions intersecting ciliome genes in cases as compared with controls.Conclusion:Our data provide strong evidence that large, rare deletions increase the risk of Down syndrome-associated atrioventricular septal defects, whereas large, common copy-number variants do not appear to increase the risk of Down syndrome-associated atrioventricular septal defects. The genetic architecture of atrioventricular septal defects is complex and multifactorial in nature.Genet Med 17 7, 554-560.

AB - Purpose:The goal of this study was to identify the contribution of large copy-number variants to Down syndrome-associated atrioventricular septal defects, the risk for which in the trisomic population is 2,000-fold more as compared with that of the general disomic population.Methods:Genome-wide copy-number variant analysis was performed on 452 individuals with Down syndrome (210 cases with complete atrioventricular septal defects; 242 controls with structurally normal hearts) using Affymetrix SNP 6.0 arrays, making this the largest heart study conducted to date on a trisomic background.Results:Large, common copy-number variants with substantial effect sizes (OR > 2.0) do not account for the increased risk observed in Down syndrome-associated atrioventricular septal defects. By contrast, cases had a greater burden of large, rare deletions (P <0.01) and intersected more genes (P <0.007) as compared with controls. We also observed a suggestive enrichment of deletions intersecting ciliome genes in cases as compared with controls.Conclusion:Our data provide strong evidence that large, rare deletions increase the risk of Down syndrome-associated atrioventricular septal defects, whereas large, common copy-number variants do not appear to increase the risk of Down syndrome-associated atrioventricular septal defects. The genetic architecture of atrioventricular septal defects is complex and multifactorial in nature.Genet Med 17 7, 554-560.

KW - atrioventricular septal defects

KW - ciliome

KW - congenital heart defect

KW - copy-number variation

KW - Down syndrome

UR - http://www.scopus.com/inward/record.url?scp=84942802683&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84942802683&partnerID=8YFLogxK

U2 - 10.1038/gim.2014.144

DO - 10.1038/gim.2014.144

M3 - Article

C2 - 25341113

AN - SCOPUS:84942802683

VL - 17

SP - 554

EP - 560

JO - Genetics in Medicine

JF - Genetics in Medicine

SN - 1098-3600

IS - 7

ER -