https://doi.org/10.1038/ng.534

A neurodevelopmental geneticist explores how one mutation can lead to multiple diseases.

Work in psychiatric genetics has revealed that certain deletions or duplications of small chromosomal regions — termed copy-number variants (CNVs) — drastically increase the risk of disorders such as autism and schizophrenia. The findings are contributing to a shift in how we think about the cause of disease: away from a model involving a combination of common gene variants in each individual to one in which single, rare mutations in any of a large number of genes lead to disease in a high proportion of people.

However, it has come as a major surprise that many such mutations increase the risk not just of one disorder but of many — suggesting that primary insults to neural development may manifest themselves differently from one individual to another.

Evan Eichler at the University of Washington in Seattle and his colleagues investigated one possible reason: genetic background effects (S. Girirajan et al. Nature Genet. 42, 203–209; 2010). Previous studies had identified CNVs at a specific location on chromosome 16 in patients with autism or schizophrenia. Eichler et al. found that such mutations are also enriched in patients with developmental delay or cognitive disabilities.

Interestingly, among these cases, the researchers found a sixfold increase in the occurrence of a second CNV in other parts of the genome. Notably, these patients had a different set of symptoms from those with either single CNV alone.

This kind of modifying effect — due to additional, rare mutations in the background — is probably typical in human biology. With a growing understanding of the observable effects of mutations, it will be important and, in the near future, feasible to take each individual's entire genetic make-up into account when studying the roots of psychiatric disease.

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