Copy Number Variation (CNV) disease refers to genetic conditions caused by an abnormal number of copies of specific DNA segments in a person’s genome. These variations, involving extra or missing genetic material, contribute to a variety of health issues. Understanding CNV diseases helps explain why some individuals develop complex medical conditions, from developmental delays to neurological disorders.
Understanding Copy Number Variations
Copy Number Variations (CNVs) are structural changes in the genome where segments of DNA, typically 1 kilobase (kb) or larger, are either duplicated (extra copies) or deleted (missing copies). These variations range in size from a few hundred base pairs to several megabases, encompassing entire genes or multiple genes.
CNVs are distinct from single nucleotide polymorphisms (SNPs), which involve a change in a single DNA building block. While some CNVs are common and do not cause health problems, others can lead to disease. CNVs can affect approximately 4.8% to 9.5% of the human genome in a given individual.
How CNVs Lead to Disease
CNVs cause disease primarily through “gene dosage,” where the number of gene copies directly impacts the amount of protein produced. Too many copies of a gene can lead to an excess of its protein, while too few copies result in an insufficient amount. Both scenarios disrupt normal cellular processes and can lead to disease.
For instance, a gene deletion can cause haploinsufficiency, where one remaining copy is not enough for proper function. Conversely, a gene duplication can lead to overexpression, where an abundance of the gene’s product becomes detrimental. CNVs can also disrupt genes by breaking them apart or affect regulatory regions that control gene expression. The specific location, size, and genes encompassed by a CNV determine its potential health impact.
Common CNV-Related Conditions
Copy Number Variations are linked to a wide array of human conditions.
DiGeorge Syndrome
Also known as 22q11.2 deletion syndrome, this condition is caused by a deletion on chromosome 22, leading to various developmental issues.
Williams Syndrome
This syndrome results from a deletion on chromosome 7q11.23, often manifesting as distinct facial features, heart problems, and unique cognitive profiles.
Prader-Willi and Angelman Syndromes
Both are associated with deletions or duplications in the 15q11-q13 region of chromosome 15, with the specific parental origin of the CNV determining which syndrome develops.
Autism Spectrum Disorder and Intellectual Disability
Certain forms have been linked to recurrent CNVs in regions such as 1q21, 3q29, 15q11.2, 15q13.3, 16p11.2, and 22q11.2.
Huntington’s Disease
This neurological disorder is caused by an abnormal increase in a specific three-base-pair repeat within the HTT gene, with more repeats often correlating with earlier disease onset.
Detecting CNV Diseases
Detecting CNVs in a clinical setting involves advanced genetic testing methods. Chromosomal microarray (CMA) is a primary technique used to identify deletions and duplications across the entire genome, offering higher resolution than older methods and detecting changes as small as a few kilobases.
Older methods like fluorescence in situ hybridization (FISH) or karyotyping detect larger chromosomal abnormalities, typically in the megabase range, but lack sensitivity for smaller CNVs. Next-generation sequencing (NGS) technologies also detect smaller CNVs and provide detailed sequence information. Genetic counseling is typically offered alongside these tests to help individuals and families understand the results and their implications.