Copy Number Variation

Copy number variation (CNV) is a form of structural variation in which segments of DNA are present in differing numbers of copies between individuals — typically through deletions that reduce copies or duplications that increase them. CNVs span from kilobases to megabases, account for a substantial portion of human genetic diversity, and can influence phenotype by changing the dosage of the genes they encompass.

Definition

Copy number variation is a structural variant in which a DNA segment, conventionally one kilobase or larger, is present in a variable number of copies relative to a reference genome, arising chiefly through deletions (copy loss) and duplications (copy gain).

Scope

This topic covers gains and losses of DNA copies as a distinct, dosage-defined class of structural variation: how CNVs arise, how their dosage effects relate to phenotype, and how they are detected and interpreted. It complements the broader sibling topic on chromosomal structural variation, which also includes balanced rearrangements. This is reference material on the concept, not clinical management guidance.

Key concepts

• Copy gain (duplication) and copy loss (deletion)
• Gene dosage
• Dosage sensitivity, haploinsufficiency, and triplosensitivity
• Non-allelic homologous recombination
• Recurrent versus non-recurrent CNVs
• Benign copy number polymorphism
• Chromosomal microarray detection
• Incomplete penetrance and variable expressivity

Mechanisms

Copy number changes arise mainly through recombination- and replication-based mechanisms: non-allelic homologous recombination between flanking segmental duplications produces recurrent CNVs with consistent breakpoints, while replication errors and end-joining produce non-recurrent CNVs of variable size (Hastings et al., 2009). A CNV affects phenotype principally by altering gene dosage — deleting a dosage-sensitive (haploinsufficient) gene or increasing copies of a triplosensitive one — and may also disrupt or fuse genes at its breakpoints. Many CNVs are common, benign polymorphisms, and genome-wide studies have shown they cover a meaningful fraction of the genome and contribute to variation in gene expression (Wellcome Trust Case Control Consortium, 2010; Feuk et al., 2006).

Clinical relevance

CNVs are a recognised cause of developmental and neuropsychiatric conditions and of recurrent genomic disorders, and chromosomal microarray is a common first-tier test in their evaluation. Interpreting a CNV requires distinguishing benign polymorphisms from dosage changes affecting dosage-sensitive genes, and some pathogenic CNVs show incomplete penetrance and variable expressivity. This topic describes how CNVs arise and are assessed and is not a basis for individual diagnostic or treatment decisions.

Epidemiology

Copy number variants are a common form of human genetic variation, collectively spanning a substantial proportion of the genome; large surveys found that most common CNVs are benign and that they account for a measurable share of heritable differences in gene expression (Wellcome Trust Case Control Consortium, 2010).

Debates

Why do some pathogenic CNVs show variable outcomes?

Certain disease-associated CNVs show incomplete penetrance and variable expressivity, with carriers ranging from unaffected to severely affected; this is attributed to modifying variants, second hits, and environmental factors, complicating prediction of outcome from the CNV alone.

Seminal works

• hastings-2009
• wtccc-2010
• feuk-2006

Frequently asked questions

How is copy number variation related to structural variation?

Copy number variation is a subset of structural variation, specifically the unbalanced changes — deletions and duplications — that alter the number of copies of a DNA segment, as opposed to balanced rearrangements such as inversions and translocations.

Are all copy number variants harmful?

No. Many CNVs are common, benign polymorphisms with no apparent effect. Clinical significance depends on the size and location of the change and whether it alters the dosage of genes that are sensitive to copy number.