Copy Number Variation: Methods and Clinical Applications

Pös, Ondrej; Radvánszky, Ján; Styk, Jakub; Pös, Zuzana; Buglyó, Gergely; Kajsik, Michal; Budiš, Jaroslav; Nagy, Bálint; Szemes, Tomáš

doi:10.3390/app11020819

Cited by 42 publications

(43 citation statements)

References 108 publications

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“…One may argue that clinical applications of CNV detection, particularly in the field of oncogenetics and severe congenital anomalies, were among the first in the history of genetic testing and are still in general use. However, considering the technical innovations now allowing population-scale genome-wide CNV screening, together with the still widening spectrum of known biological roles of CNVs, we have yet to take full advantage of CNV detection in routine clinical care [ 26 ]. In favor of this point-of-view, official systematic guidelines on the interpretation of CNVs and their classification by clinical impact were issued by the American College of Medical Genetics and Genomics for the first time only in 2019 [ 27 ].…”

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confidence: 99%

DNA copy number variation: Main characteristics, evolutionary significance, and pathological aspects

et al. 2021

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Copy number variants (CNVs) were the subject of extensive research in the past years. They are common features of the human genome that play an important role in evolution, contribute to population diversity, development of certain diseases, and influence host–microbiome interactions. CNVs have found application in the molecular diagnosis of many diseases and in non-invasive prenatal care, but their full potential is only emerging. CNVs are expected to have a tremendous impact on screening, diagnosis, prognosis, and monitoring of several disorders, including cancer and cardiovascular disease. Here, we comprehensively review basic definitions of the term CNV, outline mechanisms and factors involved in CNV formation, and discuss their evolutionary and pathological aspects. We suggest a need for better defined distinguishing criteria and boundaries between known types of CNVs.

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confidence: 99%

DNA copy number variation: Main characteristics, evolutionary significance, and pathological aspects

et al. 2021

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“…Thanks to the many genomic initiatives around the world, CGH and SNP arrays or sequencing experiments generate a tremendous amount of human structural variations leading to the need of specific annotations tools. There are several online tools available like VEP ( 23 ) or DeAnnCNV ( 24 ) (for review see ( 25 )). Based on these annotations, SV prioritization is gaining interest with a few programs like SVScore ( 26 ) and recently machine learning methods paving the future of SV interpretation ( 27 , 28 ).…”

Section: Discussion and Future Updatesmentioning

confidence: 99%

AnnotSV and knotAnnotSV: a web server for human structural variations annotations, ranking and analysis

Geoffroy

Guignard²,

Kress

et al. 2021

Nucleic Acids Research

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With the dramatic increase of pangenomic analysis, Human geneticists have generated large amount of genomic data including millions of small variants (SNV/indel) but also thousands of structural variations (SV) mainly from next-generation sequencing and array-based techniques. While the identification of the complete SV repertoire of a patient is getting possible, the interpretation of each SV remains challenging. To help identifying human pathogenic SV, we have developed a web server dedicated to their annotation and ranking (AnnotSV) as well as their visualization and interpretation (knotAnnotSV) freely available at the following address: https://www.lbgi.fr/AnnotSV/. A large amount of annotations from >20 sources is integrated in our web server including among others genes, haploinsufficiency, triplosensitivity, regulatory elements, known pathogenic or benign genomic regions, phenotypic data. An ACMG/ClinGen compliant prioritization module allows the scoring and the ranking of SV into 5 SV classes from pathogenic to benign. Finally, the visualization interface displays the annotated SV in an interactive way including popups, search fields, filtering options, advanced colouring to highlight pathogenic SV and hyperlinks to the UCSC genome browser or other public databases. This web server is designed for diagnostic and research analysis by providing important resources to the user.

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“…For gene variants caused by SNPs and indels, the qPCR amplified product can be submitted for genome sequencing 13 . In the investigation of copy number variants, a two-step approach can be adopted 37 . Firstly, CNV calls observed in this study may be checked against an alternative benchmark such as digital droplet PCR (ddPCR) 38 .…”

Section: Future Workmentioning

confidence: 99%

“…Firstly, CNV calls observed in this study may be checked against an alternative benchmark such as digital droplet PCR (ddPCR) 38 . Secondly, where discordance in CNV calling persists, methods such as XL-PCR can be adopted to identify the presence of CYP2D6/CYP2D7 hybrid states, with submitting samples for whole-genome sequencing 37 being an option. Investigation of copy number variants may require amplification of region spanning across the gene of interest.…”

Section: Future Workmentioning

confidence: 99%

Validation of a multi-gene qPCR-based pharmacogenomics panel across major ethnic groups in Singapore and Indonesia

Kothary¹,

Mahendra²,

Tan³

et al. 2021

Preprint

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Background: With up to 70% of adverse drug reactions (ADRs) having high genetic associations, the clinical utility of pharmacogenomics (PGx) has been gaining traction. Nala PGx Core is a multi-gene qPCR-based panel that comprises 18 variants and 2 CYP2D6 Copy Number markers across 4 pharmacogenes - CYP2C9, CYP2C19, CYP2D6 and SLCO1B1. Objectives: In this study, we validated the performance of Nala PGx Core against benchmark methods, on the Singaporean and Indonesian populations. Additionally, we examined the allele and diplotype frequencies across 5 major ethnic groups present in these populations namely, Indonesians, Chinese, Malays, Indians and Caucasians. Methods: Human gDNA samples, extracted from the buccal swabs of 246 participants, were tested on Nala PGx Core and two chosen benchmarks, Agena VeriDose Core and CYP2D6 Copy Number Variation (CNV) Panel, and TaqMan DME Genotyping Assays. Performance was evaluated based on assay robustness, precision and accuracy at the genotype- and diplotype-level. Results: Nala PGx Core demonstrated high genotype- and diplotype-level call rates of >97% and >95% respectively in CYP2D6, and 100% for CYP2C9, CYP2C19 and SLCO1B1. A precision rate of 100% was observed on both intra- and inter-precision studies. Variant-level concordance to the benchmark methods was >96.9% across all assays, which consequently resulted in a diplotype-level concordance of >94.7% across CYP2C9, CYP2C19 and CYP2D6. Overall, the allele frequencies of CYP2D6*10 and CYP2D6*36 were higher in our cohort as compared to previous records. Notably, CYP2D6 copy number variation (CNV) analysis demonstrated a CYP2D6 *10/*36 frequency of 26.5% amongst the Indonesian cohort. Conclusion: Nala PGx Core produced robust and accurate genotyping when compared to other established benchmarks. Furthermore, the panel successfully characterized alleles of clinical relevance in the Singaporean and Indonesian populations such as CYP2D6*10 and CYP2D6*36, suggesting its potential for adoption in clinical workflows regionally.

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Copy Number Variation: Methods and Clinical Applications

Cited by 42 publications

References 108 publications

DNA copy number variation: Main characteristics, evolutionary significance, and pathological aspects

DNA copy number variation: Main characteristics, evolutionary significance, and pathological aspects

AnnotSV and knotAnnotSV: a web server for human structural variations annotations, ranking and analysis

Validation of a multi-gene qPCR-based pharmacogenomics panel across major ethnic groups in Singapore and Indonesia

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