RT Journal Article SR Electronic T1 Analysis of copy number variants on chromosome 21 in Down syndrome-associated congenital heart defects JF bioRxiv FD Cold Spring Harbor Laboratory SP 093583 DO 10.1101/093583 A1 Benjamin L. Rambo-Martin A1 Jennifer G. Mulle A1 David J. Cutler A1 Lora J.H. Bean A1 Tracie C. Rosser A1 Kenneth J. Dooley A1 Clifford Cua A1 George Capone A1 Cheryl L. Maslen A1 Roger H. Reeves A1 Stephanie L. Sherman A1 Michael E. Zwick YR 2017 UL http://biorxiv.org/content/early/2017/05/01/093583.abstract AB One in five people with Down syndrome (DS) are born with an atrioventricular septal defect (AVSD), an incidence 2,000 times higher than in the euploid population. The genetic loci that contribute to this risk are poorly understood. In this study, we tested two hypotheses: 1) individuals with DS carrying chromosome 21 copy number variants (CNVs) that interrupt exons may be protected from AVSD, because these CNVs return AVSD susceptibility loci back to disomy, and 2) individuals with DS carrying chromosome 21 genes spanned by microduplications are at greater risk for AVSD because these microduplications boost the dosage of AVSD susceptibility loci beyond a tolerable threshold. We tested 198 case individuals with DS+AVSD and 211 control individuals with DS and a normal heart using a custom microarray with dense probes tiled on chromosome 21 for array CGH. We found that neither an individual chromosome 21 CNV nor any individual gene intersected by a CNV was associated with AVSD in DS. Burden analyses revealed that African American controls had more bases covered by rare deletions than did African American cases. Inversely, we found that Caucasian cases had more genes intersected by rare duplications than did Caucasian controls. Pathway analyses indicated copy number perturbations of genes involved in protein heterotrimerization and histone methylating proteins. Finally, we showed that previously DS+AVSD-associated common CNVs on chromosome 21 are likely false positives. This research adds to the swell of evidence indicating that DS-associated AVSD is similarly heterogeneous, as is AVSD in the euploid population.