In the last decades, the expansion in the field of molecular biology has brought great advances in human and medical genetics. Among these advances is the identification of structural variants in the genome, such as Copy number variations (CNVs), which can be triggered by several factors, as errors during recombination, replication, or DNA repair processes.
What are CNVs?
CNVs are a source of genetic diversity in humans, integrating the process of evolution and adaptation of the species. CNVs are called genomic segments greater than 50 base pairs (bp) that differ in the number of copies, based on the ploidy of the human species. Therefore, CNVs are characterized by duplications, also known as gain or increase in genomic content, or deletions also called loss or decrease in genomic content.
What do they cause?
The implication of CNVs in relevant clinical manifestations depends on the region involved, which can be since benign polymorphic variants to Mendelian or sporadic traits or even being associated with complex diseases due to molecular mechanisms such as gene dosage, gene disruption, gene fusion or even positional effect. Thus, detailed clinical characterization is extremely important, being fundamental to genotype-phenotype correlation.
How to analyze them?
There are still difficulties and delays in the interpretation of CNVs to distinguish them among those that portray genetic diversity in humans or those that are related to specific clinical conditions. Thus, CNVs can be common (frequent) or rare, being rare CNVs the most difficult to interpret and classify. They are the ones of higher clinical interest since it is expected that an alteration linked to a rare condition will also be not frequent in the general population.
Therefore, the interpretation of the pathogenicity of CNVs can be challenging and depends a lot on the frequency of information presents in control samples of the general population such as in the DGV (Database of Genomic Variants) or “in house” databases, and in the databases of clinically relevant CNVs previously reported. The most used are:
- OMIM (Online Mendelian Inheritance in Man);
- DECIPHER (DatabasE of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources);
- ClinGen (Clinical Genome Resource).
In addition, the interpretation requires considering some important genetic events such as the occurrence of a “de novo” dominant CNVs, inherited dominant, genomic imprinting, X chromosome-linked, recessive inheritance, dominant inheritance, “two-hit” CNV model and mosaicism. There is other important information such as size, genomic location (exons and introns), gene content (especially regarding sensitivity, function, expression pattern and association of known genetic conditions), the type of consequence of the mutation (loss or gain of function ) and the number of copies (duplication or deletion), which should be considered.
However, because its a study area in full expansion, the databases are constantly updated, and a result that is not found in regions of interest today, in the future can be re-analyzed and contribute with new evidence related to the hypothesis diagnosis.
Thus, the knowledge and study of CNVs have shown to be of high clinical importance, however, it requires optimized methods of investigation, detailed clinical data, as well as the analysis and interpretation of data must be performed with accuracy and expertise, in order to have the objective diagnostic conclusion. Thus, a team with a greater multidisciplinary scope can contribute to greater efficiency in the percentage of diagnostic completion.
About the author: Ilária Cristina Sgardioli has a degree in Biological Sciences with a specialization Latu Sensu in Molecular Genetics and Cytogenetics, a master in Biomedical Sciences and a PhD in Sciences with an emphasis in Medical Genetics from the Faculty of Medical Sciences at University of Campinas.
 Kearney HM, Thorland EC, Brown KK, et al. (2011) American College of Medical Genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants. Genet Med 13:680-685
 Zarrei M, MacDonald JR, Merico D, Scherer SW (2015) A copy number variation map of the human genome. Nat Rev Genet 16:172-183
 Zhang F, Gu W, Hurles ME, Lupski JR (2009) Copy number variation in human health, disease, and evolution. Annu Rev Genomics Hum Genet 10:451-481