Language
English
Publication Date
10-29-2024
Journal
bioRxiv
DOI
10.1101/2024.10.27.620363
PMID
39553991
PMCID
PMC11565771
PubMedCentral® Posted Date
10-29-2024
PubMedCentral® Full Text Version
Pre-Print
Abstract
Background: Copy number variation (CNV) is a class of genomic Structural Variation (SV) that underlie genomic disorders and can have profound implications for health. Short-read genome sequencing (sr-GS) enables CNV calling for genomic intervals of variable size and across multiple phenotypes. However, unresolved challenges include an overwhelming number of false-positive calls due to systematic biases from non-uniform read coverage and collapsed calls resulting from the abundance of paralogous segments and repetitive elements in the human genome.
Methods: To address these interpretative challenges, we developed VizCNV. The VizCNV computational tool for inspecting CNV calls uses various data signal sources from sr-GS data, including read depth, phased B-allele frequency, as well as benchmarking signals from other SV calling methods. The interactive features and view modes are adept for analyzing both chromosomal abnormalities [e.g., aneuploidy, segmental aneusomy, and chromosome translocations], gene exonic CNV and non-coding gene regulatory regions. In addition, VizCNV includes a built-in filter schema for trio genomes, prioritizing the detection of impactful germline CNVs, such as de novo CNVs. Upon computational optimization by fine-tuning parameters to maximize sensitivity and specificity, VizCNV demonstrated approximately 83.8% recall and 77.2% precision on the 1000 Genome Project data with an average coverage read depth of 30x.
Results: We applied VizCNV to 39 families with primary immunodeficiency disease without a molecular diagnosis. With implemented build-in filter, we identified two de novo CNVs and 90 inherited CNVs >10 kb per trio. Genotype-phenotype analyses revealed that a compound heterozygous combination of a paternal 12.8 kb deletion of exon 5 and a maternal missense variant allele of DOCK8 are likely the molecular cause of one proband.
Conclusions: VizCNV provides a robust platform for genome-wide relevant CNV discovery and visualization of such CNV using sr-GS data.
Keywords
deletions, duplications, structural variation, Mendelian diseases, Genomic disorders, trisomy 21, runs of homozygosity
Published Open-Access
yes
Recommended Citation
Mehaffey, Michele G; Hwang, James Paul; Jhangiani, Shalini N; et al., "Vizcnv: An Integrated Platform for Concurrent Phased Baf and Cnv Analysis With Trio Genome Sequencing Data" (2024). Faculty, Staff and Students Publications. 8570.
https://digitalcommons.library.tmc.edu/baylor_docs/8570