Our genetic blueprint is not a fixed code, as it contains variations that account for our individuality. Some of these variations involve large-scale structural changes to our DNA. The process of identifying these changes, known as CNV detection, allows for a deeper understanding of the human genome by identifying differences in the number of copies of specific DNA segments. This analysis improves our comprehension of human health and disease.
Defining Copy Number Variations
Copy Number Variations (CNVs) are a structural variant in our DNA characterized by deletions or duplications of large genomic segments. A deletion means a segment of DNA is missing, while a duplication means there are extra copies. These variations are distinct from smaller changes like Single Nucleotide Polymorphisms (SNPs), which involve only a single DNA building block. CNVs are much larger, affecting anywhere from a few thousand to many millions of DNA base pairs.
These structural changes can arise from errors when cells divide and replicate their DNA. During recombination, for example, an unequal exchange of DNA between chromosomes can lead to one receiving an extra copy of a gene while the other loses it. These events contribute to the natural genetic diversity seen across the human population.
Impact of CNVs on Health and Development
The presence of CNVs is a normal aspect of human genetic diversity, and many have no discernible effect on health. These benign variations contribute to the subtle differences between people. However, a CNV can have a significant impact on health and development depending on its characteristics.
The consequences of a CNV depend on its size, its location in the genome, and which genes are involved. Some CNVs are linked to conditions like autism spectrum disorder and intellectual disability, and they can also influence susceptibility to certain cancers and autoimmune diseases. Whether a CNV is inherited or arises as a new de novo mutation also plays a part in its effect.
Techniques for Identifying CNVs
Several laboratory techniques are used to detect CNVs by comparing a patient’s DNA to a reference sample to identify gains or losses of genetic material. Common approaches include:
- Microarray-based analysis, using technologies like array Comparative Genomic Hybridization (aCGH) and SNP arrays.
- Quantitative PCR (qPCR), which measures the copy number of a small, specific DNA region and is often used for validation.
- Next-Generation Sequencing (NGS), including Whole Genome Sequencing (WGS) and Whole Exome Sequencing (WES).
NGS techniques identify CNVs by analyzing the depth of sequencing reads across the genome, where an increase or decrease in read depth can indicate a duplication or deletion. Regardless of the technology, a computational step called bioinformatics analysis is required. This analysis processes the large datasets to accurately identify the boundaries and copy number of any detected variants.
Clinical Uses of CNV Detection
Detecting CNVs has practical applications across medicine. In prenatal care, CNV analysis screens for chromosomal abnormalities and specific syndromes that can affect fetal development. This provides expectant parents with important information during pregnancy.
For children and adults, CNV detection is a diagnostic tool used to investigate the genetic causes of developmental delays, intellectual disabilities, and congenital anomalies. Identifying a specific CNV can provide a diagnosis for a previously unexplained condition and help guide management and support.
In oncology, CNV analysis examines the genetic makeup of tumors. Certain CNVs in cancer cells, like the amplification of the HER2 gene in some breast cancers, can provide prognostic information and guide targeted therapies. This detection of somatic CNVs helps personalize cancer treatment and monitor disease response.
Interpreting CNV Detection Findings
Identifying a CNV is the initial step, but interpreting its meaning is a complex process. Geneticists classify CNVs into categories based on their likely impact: pathogenic, likely pathogenic, benign, likely benign, or a variant of uncertain significance (VUS). A VUS classification means there is not enough evidence to determine if the CNV is related to a health condition.
To aid interpretation, clinicians use international databases like ClinVar and DECIPHER, which collect information on CNVs and their observed effects. These resources and scientific literature help determine a variant’s clinical significance. The process is challenged by factors like incomplete penetrance, where not everyone with a pathogenic CNV develops the associated condition.
Another complicating factor is variable expressivity, where individuals with the same CNV show different symptoms. For these reasons, family studies analyzing the DNA of relatives can be helpful. Genetic counseling is also part of the process, helping individuals and families understand the implications of CNV findings for their health and future.