Copy number variations, or CNVs, represent a source of genetic diversity involving alterations to the DNA, specifically changes in the number of copies of a particular segment of the genome. While genes were once thought to be present in two copies, it is now understood that large sections of DNA can vary. To conceptualize this, think of the human genome as an instruction manual where a CNV is like having a sentence either missing or accidentally copied into the text.
These structural differences are common, and many are harmless, simply contributing to a person’s unique genetic makeup without affecting their health. However, some CNVs can be associated with specific traits or health conditions, helping to explain the complex relationship between our genes and health.
The Genetic Basis of CNVs
A Copy Number Variation (CNV) is a type of structural variant where segments of DNA are not present in the typical two-copy state. This can happen in two primary ways. A deletion occurs when a segment of a chromosome, which can range from a small piece to a larger section with multiple genes, is missing. This results in having only one copy, or in rare cases zero copies, of that genetic material.
Conversely, a duplication happens when a segment of a chromosome is repeated, leading to extra copies of that genetic material. Instead of the normal two copies, an individual might have three, four, or even more. To extend the analogy of a recipe book, a deletion is like a recipe being torn out, while a duplication is like a recipe being photocopied and stuck back in.
The size of these variations can differ greatly, from relatively small segments of DNA to large regions spanning millions of DNA base pairs. These changes can encompass numerous genes or fall in non-coding regions of the genome. The presence of these deletions or duplications can lead to an imbalance in the amount of genetic information, which may influence how certain genes function.
Origins and Inheritance of CNVs
Copy Number Variations can arise in two main ways: they can be inherited from a parent or occur as a new, spontaneous event. Inherited CNVs are passed down through germ cells—the sperm or egg—from a parent to their child. In these cases, the same deletion or duplication in the child’s genetic makeup can also be found in the genome of one of the parents.
In contrast, some CNVs are classified as de novo, meaning “from the new.” A de novo CNV is a genetic alteration that appears for the first time in an individual and is not present in the genetic material of either parent. These variations are the result of spontaneous events during the formation of reproductive cells or in early embryonic development.
The formation of CNVs is often linked to processes during DNA replication and recombination. Errors can occur when DNA is being copied, or recombination can lead to unequal exchanges between chromosomes, resulting in changes to the copy number. Studies show that while a significant portion of CNVs are inherited, de novo CNVs also account for a substantial number of cases.
Detecting Copy Number Variations
Identifying CNVs requires specialized genetic testing that can analyze a person’s DNA at a high resolution. The primary method for this is Chromosomal Microarray (CMA). CMA is a technique that scans an individual’s entire genome to detect small deletions and duplications of DNA segments that are too small to be seen with a traditional microscope-based karyotype test.
The CMA test works by comparing a patient’s DNA sample to a reference DNA sample on a microarray chip. By measuring the fluorescence intensity, the test can determine if there are regions in the patient’s genome with more or less DNA than the reference sample, thus identifying CNVs.
While CMA is a standard tool, other technologies can also identify these variations. Next-generation sequencing (NGS), particularly whole-genome sequencing (WGS), provides a base-by-base view of the genome and can detect a wide range of CNVs. Gene panels, which focus on a targeted set of genes known to be associated with specific conditions, can also be used to find CNVs within those particular genes. CMA is frequently used as a first-line test for individuals with developmental delays or congenital anomalies.
Health Implications of CNVs
The impact of a Copy Number Variation on an individual’s health is largely determined by its size, location in the genome, and the specific genes involved. Many CNVs are found in the general population and have no observable consequence on health. These are often classified as benign variants.
Conversely, some CNVs are known to be pathogenic, meaning they are directly associated with a medical condition. These can cause a wide array of genomic disorders, including developmental delays, intellectual disability, and autism spectrum disorder. For instance, well-documented microdeletions or microduplications in specific chromosomal regions, such as 1q21.1 or 15q13.3, are linked to a range of neurodevelopmental disorders.
A significant challenge in clinical genetics is the classification of a Variant of Unknown Significance (VUS). A VUS is a CNV that has been identified, but there is not enough scientific evidence to determine whether it is benign or pathogenic. Over time, as more research is conducted and more individuals with the same VUS are studied, it may be reclassified.
The interpretation of a CNV’s impact requires careful analysis. Factors such as whether the variation was inherited from a healthy parent can influence its classification. A CNV inherited from an unaffected parent may be more likely to be benign, though this is not always the case.
Navigating a CNV Diagnosis
Receiving a diagnosis involving a Copy Number Variation can bring up many questions. The first step after a CNV is identified is often a consultation with a genetic counselor. Genetic counselors are healthcare professionals with specialized training who help people understand complex genetic information, explain test results, discuss potential health implications, and provide information about inheritance patterns.
Genetic counselors help put the results into the context of the individual’s or family’s health. They can clarify the differences between pathogenic variants, benign variants, and Variants of Uncertain Significance (VUS). This guidance is important for making informed decisions about medical management.
Management for a CNV is focused on addressing the specific symptoms or health issues associated with it, rather than “curing” the underlying genetic change. For example, if a CNV is linked to developmental delays, interventions may include speech, occupational, or physical therapy. The goal is to provide supportive care tailored to the individual’s needs.
For families, understanding the origin of the CNV—whether it was inherited or occurred de novo—is an important piece of information provided during genetic counseling. Support and advocacy groups can also be valuable resources, connecting families with others who have similar experiences and providing access to information and resources.