JAX-CNV: A Whole-genome Sequencing-based Algorithm for Copy Number Detection at Clinical Grade Level

Wan-Ping Lee; Qihui Zhu; Xiaofei Yang; Silvia Liu; Eliza Cerveira; Mallory Ryan; Adam Mil-Homens; Lauren Bellfy; Kai Ye; Charles Lee; Chengsheng Zhang

doi:10.1016/j.gpb.2021.06.003

JAX-CNV: A Whole-genome Sequencing-based Algorithm for Copy Number Detection at Clinical Grade Level

Genomics Proteomics Bioinformatics. 2022 Dec;20(6):1197-1206. doi: 10.1016/j.gpb.2021.06.003. Epub 2022 Jan 25.

Authors

Affiliations

¹ Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China; The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA; School of Cyber Science and Engineering, Xi'an Jiaotong University, Xi'an 710049, China; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: wan-ping.lee@pennmedicine.upenn.edu.
² The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA.
³ The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA; School of Computer Science and Technology, Faculty of Electronic and Information Engineering, Xi'an Jiaotong University, Xi'an 710049, China; MOE Key Lab for Intelligent Networks & Networks Security, Faculty of Electronic and Information Engineering, Xi'an Jiaotong University, Xi'an 710049, China.
⁴ Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China; MOE Key Lab for Intelligent Networks & Networks Security, Faculty of Electronic and Information Engineering, Xi'an Jiaotong University, Xi'an 710049, China.
⁵ Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China; The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA; Department of Life Sciences, Ewha Womans University, Seoul 03760, South Korea.
⁶ Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China; The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA. Electronic address: cszhang99@xjtu.edu.cn.

Abstract

We aimed to develop a whole-genome sequencing (WGS)-based copy number variant (CNV) calling algorithm with the potential of replacing chromosomal microarray assay (CMA) for clinical diagnosis. JAX-CNV is thus developed for CNV detection from WGS data. The performance of this CNV calling algorithm was evaluated in a blinded manner on 31 samples and compared to the 112 CNVs reported by clinically validated CMAs for these 31 samples. The result showed that JAX-CNV recalled 100% of these CNVs. Besides, JAX-CNV identified an average of 30 CNVs per individual, respresenting an approximately seven-fold increase compared to calls of clinically validated CMAs. Experimental validation of 24 randomly selected CNVs showed one false positive, i.e., a false discovery rate (FDR) of 4.17%. A robustness test on lower-coverage data revealed a 100% sensitivity for CNVs larger than 300 kb (the current threshold for College of American Pathologists) down to 10× coverage. For CNVs larger than 50 kb, sensitivities were 100% for coverages deeper than 20×, 97% for 15×, and 95% for 10×. We developed a WGS-based CNV pipeline, including this newly developed CNV caller JAX-CNV, and found it capable of detecting CMA-reported CNVs at a sensitivity of 100% with about a FDR of 4%. We propose that JAX-CNV could be further examined in a multi-institutional study to justify the transition of first-tier genetic testing from CMAs to WGS. JAX-CNV is available at https://github.com/TheJacksonLaboratory/JAX-CNV.

Keywords: Chromosomal microarray assay; Copy number variant; Genetic testing; JAX-CNV; Whole-genome sequencing.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Algorithms*
DNA Copy Number Variations*
Humans
Whole Genome Sequencing

Grants and funding

RF1 AG074328/AG/NIA NIH HHS/United States