A copy number variation map of the human genome

Zarrei, Mehdi; MacDonald, Jeffrey R.; Merico, Daniele; Scherer, Stephen W.

doi:10.1038/nrg3871

Cited by 793 publications

(745 citation statements)

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“…These alterations may account for adaptive or behavioural traits, may have no phenotypic effects or can underlie diseases [22]. For this reason, determining the clinical significance of CNVs is very challenging and relies heavily on both frequency information from healthy control cohorts and databases with previously reported clinically relevant CNVs.…”

Section: Cnvs: Origin Classification and Clinical Relevancementioning

confidence: 99%

“…Within this class, CNVs, which involves unbalanced rearrangements that increase or decrease the DNA content, represent the largest component by far. Currently, the size of CNVs is defined as larger than 50 bp [22] and can be limited to a single gene or include a contiguous set of genes. These structural variants encompass more polymorphic base pairs than SNPs and finally result in an altered DNA diploid status (i.e.…”

Section: Cnvs: Origin Classification and Clinical Relevancementioning

confidence: 99%

See 1 more Smart Citation

Genetics of Parkinson’s Disease: The Role of Copy Number Variations

Cognata¹,

D’Agata²,

Cavalcanti³

et al. 2016

Challenges in Parkinson's Disease

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Parkinson's disease (PD), the second most common progressive neurodegenerative disorder, was long believed to be a non-genetic sporadic origin syndrome. The identification of distinct genetic loci responsible for rare Mendelian forms of PD has represented a revolutionary breakthrough, allowing to discover novel mechanisms underlying this debilitating still incurable condition. Along with single-nucleotide polymorphisms (SNPs), other kinds of DNA molecular defects have emerged as significant disease-causing mutations, including large chromosomic structural rearrangements and copy number variations (CNVs). Due to their size variability and to the different sensitivity and resolution of detection methodologies, CNVs constitute a particular challenge in genetic studies and the pathogenetic or susceptibility impact of specific CNVs on PD is currently under debate. In this chapter, we will review the current literature and bioinformatic data describing the involvement of CNVs on PD pathobiology. We will discuss the recently highlighted role of PARK2 heterozygous CNVs, the possible common founder effects of PD gene rearrangements and the importance to map genetic breakpoints. We will also add a summary about the current available molecular methods and bioinformatics web resources to detect and interpret CNVs. Assessing the global genome-wide burden of large CNVs and elucidating the role of de novo rare structural variants on PD may reveal new candidate genes and consequently ameliorate diagnosis and counselling of mutations carriers.

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Section: Cnvs: Origin Classification and Clinical Relevancementioning

confidence: 99%

Section: Cnvs: Origin Classification and Clinical Relevancementioning

confidence: 99%

Genetics of Parkinson’s Disease: The Role of Copy Number Variations

Cognata¹,

D’Agata²,

Cavalcanti³

et al. 2016

Challenges in Parkinson's Disease

View full text Add to dashboard Cite

show abstract

“…Initially described as ranging in size from roughly a kilobase to less than five megabases, but increasingly referring to events greater than 50bp in size due to improved detection sensitivity (http://dgv.tcag.ca/dgv/app/statistics?ref=GRCh37/hg19), it is estimated that CNVs cover between 4.8 and 9.5% of the human genome 1 . They are a major cause of monogenic disease, with over 30,000 CNVs reported in the DECIPHER database to date.…”

Section: Introductionmentioning

confidence: 99%

An enhanced method for targeted next generation sequencing copy number variant detection using ExomeDepth

et al. 2017

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Copy number variants (CNV) are a major cause of disease, with over 30,000 reported in the DECIPHER database. To use read depth data from targeted Next Generation Sequencing (NGS) panels to identify CNVs with the highest degree of sensitivity, it is necessary to account for biases inherent in the data. GC content and ambiguous mapping due to repetitive sequence elements and pseudogenes are the principal components of technical variability. In addition, the algorithms used favour the detection of multi-exon CNVs, and rely on suitably matched normal dosage samples for comparison. We developed a calling strategy that subdivides target intervals, and uses pools of historical control samples to overcome these limitations in a clinical diagnostic laboratory. We compared our enhanced strategy with an unmodified pipeline using the R software package ExomeDepth, using a cohort of 109 heterozygous CNVs (91 deletions, 18 duplications in 26 genes), including 25 single exon CNVs. The unmodified pipeline detected 104/109 CNVs, giving a sensitivity of 89.62% to 98.49% at the 95% confidence interval. The detection of all 109 CNVs by our enhanced method demonstrates 95% confidence the sensitivity is ≥96.67%, allowing NGS read depth analysis to be used for CNV detection in a clinical diagnostic setting.

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“…CNV's can play an important role in human disease-by altering the structure or abundance of transcripts and proteins, for example-or can have no phenotypic effect 10,11 . Examples in many human cancers include copy number loss of the gene that codes for the tumor suppressor protein PTEN 4,12 and copy number gain in the gene that codes for the proto-oncogene EGFR 2 .…”

Section: Introductionmentioning

confidence: 99%

“…Copy number variations (CNV's)-commonly termed deletions or amplifications-are generally accepted to be any genomic variations greater than 50 bp in length that alter the amount of DNA content of a gene 10,11 . CNV's can play an important role in human disease-by altering the structure or abundance of transcripts and proteins, for example-or can have no phenotypic effect 10,11 .…”

Section: Introductionmentioning

confidence: 99%