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 perfor-mance of this CNV calling algorithm was evaluated in a blinded manner on 31 samples and com-pared 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,representing 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,sensi-tivities 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 J acksonLaboratory/JAX-CNV.

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

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;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;Department of Life Sciences,Ewha Womans University,Seoul 03760,South Korea

基因组蛋白质组与生物信息学报（英文版）

[1]Wan-Ping Lee;Qihui Zhu;Xiaofei Yang;Silvia Liu;Eliza Cerveira;Mallory Ryan;Adam Mil-Homens;Lauren Bellfy;Kai Ye;Charles Lee;Chengsheng Zhang-.JAX-CNV:A Whole-genome Sequencing-based Algorithm for Copy Number Detection at Clinical Grade Level)[J].基因组蛋白质组与生物信息学报（英文版）,2022(06):1197-1206

JAX,CMAs,Pathologists,caller,acksonLaboratory

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