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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Genet. | doi: 10.3389/fgene.2019.00819

Association of Rare Recurrent Copy Number Variants with Congenital Heart Defects based on Next Generation Sequencing Data from Family Trios

 Yichuan Liu1,  Xiao Chang1, Joseph Glessner1,  Hui-Qi Qu1, Lifeng Tian1, Dong Li1, Kenny Nguyen1,  Patrick Sleiman1, 2 and  Hakon Hakonarson1, 2, 3*
  • 1Center for Applied Genomics, Children’s Hospital of Philadelphia Research Institute, United States
  • 2Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, United States
  • 3Department of Pediatrics, Children's Hospital of Philadelphia, United States

Congenital heart defects (CHD) are a common birth defect, affecting approximately 1% of newborn children in the United States. As previously reported, a significant number of CHD are potentially attributed to altered copy number variations (CNV). However, as many genomic variants are rare, a large scale CNV triad study is necessary to characterize the genetic architecture of CHD. We used whole exome sequencing (WES) data generated by the Pediatric Cardiac Genomics Consortium (PCGC), including a discovery data set of 2,103 individuals from 760 nuclear family trios, and an independent replication set of 4,808 individuals from 1,712 trios. The candidate targets uncovered were further validated through different platforms, including the OMNI SNP array chip in 1,860 individuals and the whole genome sequencing (WGS) data in 33 trios. The genes harboring CNVs of interest were then investigated for expression alternations based on cardiac tissue RNA-seq data. We identified multiple CNVs in the WES data that associated with specific sub-phenotypes of CHD in approximately 2,400 families, including 98 de novo CNV regions. We identified five CNV loci harboring LIMS1, GCC2, RANBP2, TTC3 and MAP3K7CL, respectively, where those genes are highly expressed in human heart and/or mouse embryo heart at 15 days. Five novel CNV loci were uncovered demonstrated altered expression of the respective candidate genes involved. To our knowledge, this is the largest trio-based WES study of CHD and in addition to uncovering novel CHD targets, presents an extensive resource with the potential to provide important insights to the architecture and impact of CNVs in CHD.

Keywords: Copy number variation (CNV ), Next generation seqeuncing (NGS), Congenital heart defect (CHD), large trios study, Genomics

Received: 12 Jun 2019; Accepted: 07 Aug 2019.

Copyright: © 2019 Liu, Chang, Glessner, Qu, Tian, Li, Nguyen, Sleiman and Hakonarson. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Hakon Hakonarson, Center for Applied Genomics, Children’s Hospital of Philadelphia Research Institute, Philadelphia, 19104, Pennsylvania, United States,