Editors' ChoiceMEDICAL GENETICS

Thinking Before We Act

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Science Translational Medicine  23 Oct 2013:
Vol. 5, Issue 208, pp. 208ec175
DOI: 10.1126/scitranslmed.3007770

As clinical sequencing enters mainstream use and collection of genomic information from patients becomes routine, one consequence is the incidental discovery of genetic variations that can potentially cause disease. The issue of returning this information to the patient, with the option to act on such findings, has generated a great deal of discussion regarding the best policy to address the ethical issues and improve health outcomes. As the debate continues to play out on how to act, Dorschner and colleagues address an important, related question: How many actionable pathogenic mutations are identifiable from genetic data?

The authors began by assembling clinical experts with extensive expertise in medical genetics who then defined a set of 114 genes that were previously determined to harbor clinically actionable genetic variants. After defining very strict criteria for classifying pathogenicity for variants documented in the Human Gene Mutation Database, they screened the data from a set of 1000 individuals (half of European ancestry and half of African descent) randomly selected from the National Heart, Lung, and Blood Institute Exome Sequencing Project. Experts then manually reviewed the 239 distinct mutations identified in these individuals. Sixteen of these variants were determined to be pathogenic and were found in 18 individuals (1.8% of those surveyed).

Although only a modest number of mutations were classified as high-penetrance and pathogenic, the work brings much-needed attention to the need for better databases designed specifically to identify mutations sufficient for clinical return, the deficit of pathogenic mutations identified in non-European populations owing to insufficient studies in minority populations, the time required to review identified mutations, and the potential for misclassification of pathogenicity given current mutational databases. It is clear that more thinking is needed to develop the next generation of resources and maximize the potential for proper action on genetic findings as they emerge.

M. O. Dorschner et al., Actionable, pathogenic incidental findings in 1,000 participants’ exomes. Am. J. Hum. Genet. 93, 631–640 (2013). [Abstract]

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