Consistent count region–copy number variation (CCR-CNV): an expandable and robust tool for clinical diagnosis of copy number variation at the exon level using next-generation sequencing data

Abstract

Despite the importance of exonic copy number variations (CNVs) in human genetic diseases, reliable next-generation sequencing-based methods for detecting them are unavailable. We developed an expandable and robust exonic CNV detection tool called consistent count region (CCR)-CNV. Methods: In total, about 1000 samples of the truth set were used for validating CCR-CNV. We compared CCR-CNV performance with 2 well-known CNV tools. Finally, to overcome the limitations of CCR-CNV, we devised a combined approach. Results: The mean sensitivity and specificity of CCR-CNV alone were above 95%, which was superior to that of other CNV tools, such as DECoN and Atlas-CNV. However, low covered region and positive predictive value and high false discovery rate act as obstacles to its use in clinical settings. The combined approach showed much improved performance than CCR-CNV alone. Conclusion:In this study, we present a novel diagnostic tool that allows the identification of exonic CNVs with high confidence using various reagents and clinical next-generation sequencing platforms. We validated this method using the largest multiple ligation-dependent probe amplification-confirmed data set, including sufficient copy normal control data. The approach, combined with existing CNV tools, allows the implementation of CCR-CNV in clinical settings.

Copy Number Variations and Gene Mutations Identified by Multiplex Ligation-Dependent Probe Amplification in Romanian Chronic Lymphocytic Leukemia Patients

“…MLPA allows the detection of targeted CNVs in multiple human genes concurrently, and it has been used to screen CNVs in previous studies [ 54 , 79 ]. CNVs are regarded as a major source of structural variation in the genome and range in size from 50 base pairs (bp) to several megabases(Mbs) [ 43 , 44 ]. CNVs are estimated to contribute to 4.8–9.5% of the genome and can affect gene expression levels or induce chromosomal rearrangements causing various disorders and diseases [ 80 , 81 , 82 ].…”

“…Multiplex ligation-dependent probe amplification (MLPA) is a multiplex PCR-based assay for the detection of CNVs in genomic DNA [ 39 , 40 ]. MLPA is an accurate and reliable technique for identifying CNVs, including large and small deletions, as well as single-nucleotide aberrations, with several advantages over other detection methods [ 41 , 42 , 43 , 44 ]. MLPA has previously proven to be a useful method in other hematological malignancies such as acute myeloid leukemia [ 45 ] and lymphoblastic leukemia [ 46 ].…”

Recurrent Fever of Unknown Origin and Unexplained Bacteremia in a Patient with a Novel 4.5 Mb Microdeletion in Xp11.23-p11.22

“…Additionally, CCR-CNV, an in-house CNV prediction tool, indicated a heterozygous deletion of the X chromosome (data not shown) 9 . Inspection of the region by integrative genomics viewer (IGV) revealed reduced depth (Supplementary Fig.…”

Enhancing genomic mutation data storage optimization based on the compression of asymmetry of sparsity

“…Cross-species genome alignment methods provide genomic context for the identification of annotated gene regions for variation across species ( Samaha et al, 2021 ). In recent years, many researchers have developed a variety of rapid detection methods or tools for CNV ( Huang et al, 2021 ; Lavrichenko et al, 2021 ; Kim et al, 2022 ) and SNV ( van der Borght et al, 2015 ; Schnepp et al, 2019 ; Li et al, 2022 ). However, variant genomic mutation data are often sparse data formats that are difficult to apply with traditional compression methods.…”