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 ...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,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 lowercoverage 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.展开更多
基金supported in part by the operational funds from The First Affiliated Hospital of Xi’an Jiaotong University, Chinasupported by the National Institutes of Health, USA (Grant Nos. U24AG041689 and U54AG052427)+5 种基金supported by the National Natural Science Foundation of China (Grant Nos. 61702406 and 31671372)the National Science and Technology Major Project of China (Grant No. 2018ZX10302205)the National Key R&D Program of China (Grant Nos. 2018YFC0910400 and 2017YFC0907500)the General Financial Grant from the China Postdoctoral Science Foundation (Grant No. 2017M623178)supported in part by the Ewha Womans University Research, South Korea (Grant No. 2018-2019)supported in part by the Connecticut Bio-Innovative Fund, USA
文摘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,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 lowercoverage 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.
