CNVs: pathogenic mechanisms


chromosome-markedCNVs may be clinically neutral or pathogenic. Because they typically lead to imbalances of large genomic tracts, which often include more than one gene or regulatory region, when CNVs are pathogenic they usually cause severe or very severe diseases.

Gene deletions, duplications or multiplications as caused by CNVs may be pathogenic through one of the following mechanisms (CNVs: pathogenic mechanisms):

  1. Direct gene dosage effect: the gain or loss of a variable number of protein-coding genes will inevitably lead to strong alteration in the quantity of protein produced. Whole-gene deletions or duplications may cause haploinsufficiency or gain-of-function respectively, which may be pathogenic per se or through the alteration of the stoichiometric balance between the coded protein and other interacting proteins. Similarly, when CNV breakpoints are located within the sequence of a gene, there can be dosage alterations caused by gene interruptions (leading for instance to transcript abnormalities with consequent messenger decay) or gene fusions (which may code for aberrant proteins).
  1. Positional effect: CNVs may be pathogenic even when they do not include protein coding genes, because they can alter the dosage of regulatory regions usually upstream the gene.
  1. Transvection effect: some genomic sequences may exert a regulatory effect on sequences located not on the same chromosome but on the homologous chromosome (transvection effect). CNVs altering the dosage of such sequences may therefore impact the expression of genes located on the homologous chromosome giving a pathogenic effect.

For references see the parent page of this chapter:


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