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Birth Defects Res. 2017 Mar 1;109(4):271-295. doi: 10.1002/bdra.23609. Epub 2017 Feb 13.

Rare copy number variants in patients with congenital conotruncal heart defects.

Author information

The Department of Biomedical and Health Informatics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Division of Cardiology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Department of Ophthalmology and Human Genetics, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Statistical Genetics Section, National Human Genome Research Institute, National Institutes of Health, Baltimore, Maryland.
The Center for Applied Genomics, Department of Pediatrics, The Children's Hospital of Philadelphia, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Division of Biomedical Informatics, Cincinnati Children's Hospital, Department of Biomedical Informatics, University of Cincinnati, Cincinnati, Ohio.



Previous studies using different cardiac phenotypes, technologies and designs suggest a burden of large, rare or de novo copy number variants (CNVs) in subjects with congenital heart defects. We sought to identify disease-related CNVs, candidate genes, and functional pathways in a large number of cases with conotruncal and related defects that carried no known genetic syndrome.


Cases and control samples were divided into two cohorts and genotyped to assess each subject's CNV content. Analyses were performed to ascertain differences in overall CNV prevalence and to identify enrichment of specific genes and functional pathways in conotruncal cases relative to healthy controls.


Only findings present in both cohorts are presented. From 973 total conotruncal cases, a burden of rare CNVs was detected in both cohorts. Candidate genes from rare CNVs found in both cohorts were identified based on their association with cardiac development or disease, and/or their reported disruption in published studies. Functional and pathway analyses revealed significant enrichment of terms involved in either heart or early embryonic development.


Our study tested one of the largest cohorts specifically with cardiac conotruncal and related defects. These results confirm and extend previous findings that CNVs contribute to disease risk for congenital heart defects in general and conotruncal defects in particular. As disease heterogeneity renders identification of single recurrent genes or loci difficult, functional pathway and gene regulation network analyses appear to be more informative. Birth Defects Research 109:271-295, 2017. © 2017 Wiley Periodicals, Inc.


CNVs; congenital heart defects; conotruncal defects; copy number variants; functional analysis; pathway analysis

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