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Contribution of Copy-Number Variation to Down Syndrome–Associated Atrioventricular Septal Defects

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Contribution of Copy-Number Variation to Down Syndrome–Associated Atrioventricular Septal Defects Original Research Article © American College of Medical Genetics and Genomics © American College of Medical Genetics and Genomics ORIGINAL RESEARCH ARTICLE Contribution of copy-number variation to Down syndrome–associated atrioventricular septal defects Dhanya Ramachandran, PhD1, Jennifer G. Mulle, MPH, PhD1,2, Adam E. Locke, PhD3,9, Lora J.H. Bean, PhD1, Tracie C. Rosser, PhD1, Promita Bose, MS1, Kenneth J. Dooley, MD4, Clifford L. Cua, MD5, George T. Capone, MD6, Roger H. Reeves, PhD7, Cheryl L. Maslen, PhD8, David J. Cutler, PhD1, Stephanie L. Sherman, PhD1 and Michael E. Zwick, PhD1 Purpose: The goal of this study was to identify the contribution of contrast, cases had a greater burden of large, rare deletions (P < 0.01) large copy-number variants to Down syndrome–associated atrioven- and intersected more genes (P < 0.007) as compared with controls. tricular septal defects, the risk for which in the trisomic population is We also observed a suggestive enrichment of deletions intersecting 2,000-fold more as compared with that of the general disomic popu- ciliome genes in cases as compared with controls. lation. Conclusion: Our data provide strong evidence that large, rare dele- Methods: Genome-wide copy-number variant analysis was per- tions increase the risk of Down syndrome–associated atrioventricu- formed on 452 individuals with Down syndrome (210 cases with lar septal defects, whereas large, common copy-number variants do complete atrioventricular septal defects; 242 controls with structur- not appear to increase the risk of Down syndrome–associated atrio- ally normal hearts) using Affymetrix SNP 6.0 arrays, making this the ventricular septal defects. The genetic architecture of atrioventricular largest heart study conducted to date on a trisomic background. septal defects is complex and multifactorial in nature. Results: Large, common copy-number variants with substantial Genet Med advance online publication 23 October 2014 effect sizes (OR > 2.0) do not account for the increased risk observed Key Words: atrioventricular septal defects; ciliome; congenital in Down syndrome–associated atrioventricular septal defects. By heart defect; copy-number variation; Down syndrome INTRODUCTION reflects the combined influence of both genetic susceptibil- Congenital heart defects (CHDs) are the most prevalent and ity and environmental exposures.2,3 In humans, studies of the serious of all recognized structural birth defects, occurring in genetic architecture of CHD have implicated multiple classes 8–10 of every 1,000 live births in the United States.1 Infant death of genetic variants, including both rare3–5 and common sin- 6 7–10 Genet Med rates due to CHD are high, with 44.0 deaths per 100,000 infants gle-nucleotide variants and rare structural variants. Genes whose parents report having European ancestry and 56.2 identified as the cause of rare familial forms of CHD have been deaths per 100,000 infants whose parents report having African found to play a role in simplex forms of CHD as well. Recently, 2014 ancestry. Even with improved treatments, affected infants who using an exome sequencing approach and filtering for de novo survive birth require multiple surgeries with lengthy hospi- events, CHD susceptibility variants have been identified in his- 00 talizations. Many of these individuals experience lifelong dis- tone-modifying genes.11 abilities, such as cognitive impairment, depression, anxiety One of the most important contributors to CHD is chromo- 00 disorder, and behavioral problems, as well as reduced quality some aneuploidy.3 In the current study we have focused on tri- of life. Affected individuals also are at increased risk for sudden somy 21, or Down syndrome (DS (OMIM 190685)),12 because 26June2014 cardiac death in later childhood and adulthood. In total, CHDs it is the most common autosomal aneuploidy condition that account for more than 2.6 billion health-care dollars spent each survives to term. The prevalence of DS is ~1 in 700 live births 11September2014 year in United States. in the United States, rendering it the most commonly identified CHDs encompass a large, heterogeneous group of structural form of intellectual and development disability and a leading 10.1038/gim.2014.144 and functional abnormalities that arise during embryogen- cause of birth defects. CHD occurs in 40–50% of individu- esis. As with most complex disorders, the underlying etiology als with DS, with the majority being septal defects. The most Genetics in Medicine 1Department of Human Genetics, Emory University, Atlanta, Georgia, USA; 2Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia, 00 USA; 3Genetics and Molecular Biology Graduate Program, Graduate Division of Biological and Biomedical Sciences, Laney Graduate School, Emory University, Atlanta, Georgia, USA; 4Sibley Heart Center Cardiology, Department of Pediatrics, Children’s Hospital of Atlanta, Emory University, Atlanta, Georgia, USA; 5Heart Center, Nationwide Children’s Hospital, Columbus, Ohio, USA; 6Down Syndrome Clinic and Research Center, Kennedy Krieger Institute, Baltimore, Maryland, USA; 7Department of Physiology and McKusick 00 Nathans Institute for Genetic Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA; 8Knight Cardiovascular Institute, and Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, Oregon, USA; 9Current address: Center for Statistical Genetics and Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan, USA. Correspondence: Michael E. Zwick ([email protected]) Submitted 26 June 2014; accepted 11 September 2014; advance online publication 23 October 2014. doi:10.1038/gim.2014.144 23October2014 GENETICS in MEDICINE 1 ORIGINAL RESEARCH ARTICLE RAMACHANDRAN et al | Congenital heart defects in Down syndrome striking and severe form of DS-associated CHD is atrioven- these results suggest the genetic architecture of AVSD is multi- tricular septal defect (AVSD (OMIM 606215)),12 also known as factorial and complex, even in the DS population. atrioventricular canal defect. Although the incidence of non- syndromic AVSD in the general population is very low, 0.83 in MATERIALS AND METHODS 10,000 live births,13 ~20% of individuals with DS have complete Sample ascertainment AVSD, corresponding to a 2,000-fold increased risk. More than Details regarding the recruitment and enrollment have been 65% of all AVSD cases occur in children with DS.14 This condi- documented previously.18,22 Briefly, participants with a diag- tion typically requires surgery during the first year of life. Thus, nosis of full trisomy 21 were enrolled, with the vast majority the costs and burdens of CHD are clearly amplified among confirmed by karyotype. Individuals with partial or mosaic tri- those with DS and their families. somy 21 were not enrolled. Study participants were recruited Although trisomy 21 dramatically increases the risk of CHD through multiple centers across the United States. Protocols and AVSD, nearly 80% of children with DS do not have an were approved by institutional review boards at each par- AVSD, and 50% of children with DS are born with structur- ticipating center, and informed consent was obtained from a ally normal hearts. Therefore, the increased dosage of genes custodial parent for each participant. To minimize pheno- on chromosome 21 explains only part of the increased risk for typic heterogeneity of cases, we focused on AVSD as the most CHD in DS and suggests that additional variants throughout severe heart phenotype seen associated with DS. A single car- the genome may play a role. Thus, individuals with DS repre- diologist (K.J.D.) reviewed medical records and classified cases sent a “sensitized” population in whom genetic studies might as individuals with DS who had a complete, balanced AVSD reveal novel factors contributing to the risk for development documented most often by echocardiogram or surgical reports of CHD, and any genetic mechanisms revealed may be rel- (DS+AVSD). Controls were those with a structurally nor- evant to both trisomic and disomic individuals. Indeed, our mal heart, patent foramen ovale, or patent ductus arteriosus studies of the genetic risk factor, CRELD1 (OMIM 607170),12 (DS+NH). Medical records and echocardiography were used to have shown that the contributing missense mutations are document normal heart status. Only participants whose moth- found in both simplex euploid and DS-associated AVSD,15 ers reported being of non-Hispanic European ancestry were and that mutation of CRELD1 increases risk for CHD when included in the current study. This information was obtained expressed on a trisomic mouse background similar to trisomy from a questionnaire administered to the mothers of the chil- 21.16 This approach, i.e., using a carefully phenotyped group dren with DS by a trained interviewer. The data files are avail- of individuals with a known genetic susceptibility factor for able at the Gene Expression Omnibus repository (accession CHD, is the human equivalent of a sensitized screen used in number GSE60607). model organisms. This strategy can be successful in revealing variation and identifying novel members of pathways affecting Genotyping and CNV detection developmental or functional processes.17 Recent findings from Genomic DNA was isolated from lymphoblastoid cell lines genome-wide and chromosome 21–specific single-nucleotide using the Puregene DNA purification kit according to the
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