A semiquantitative metric for evaluating clinical actionability of incidental or secondary findings from genome-scale sequencing

As genome-scale sequencing is increasingly applied in clinical scenarios, a wide variety of genomic findings will be discovered as secondary or incidental findings, and there is debate about how they should be handled. The clinical actionability of such findings varies, necessitating standardized frameworks for a priori decision making about their analysis

DNA-mediated transformation of the basidiomycete Coprinus cinereus.

We have developed a simple and efficient transformation system for the agaric fungus, Coprinus cinereus. Protoplasts were prepared from asexual spores that harbor one or two mutations in the structural gene for tryptophan synthetase. The protoplasts can be stably transformed using the cloned Coprinus gene at a frequency of 1 in 10(4) viable protoplasts. A variety of molecular events accompanies the formation of stable transformants, including insertion of the transforming DNA at the homologous locus. The transforming DNA is stable through cell division, mating, fruiting body formation, and meiosis

A semiquantitative metric for evaluating clinical actionability of incidental or secondary findings from genome-scale sequencing

PURPOSE: As genome-scale sequencing is increasingly applied in clinical scenarios, a wide variety of genomic findings will be discovered as secondary or incidental findings, and there is debate about how they should be handled. The clinical actionability of such findings varies, necessitating standardized frameworks for a priori decision making about their analysis. Genet Med 18 5, 467–475. METHODS: We established a semiquantitative metric to assess five elements of actionability: severity and likelihood of the disease outcome, efficacy and burden of intervention, and knowledge base, with a total score from 0 to 15. Genet Med 18 5, 467–475. RESULTS: The semiquantitative metric was applied to a list of putative actionable conditions, the list of genes recommended by the American College of Medical Genetics and Genomics (ACMG) for return when deleterious variants are discovered as secondary/incidental findings, and a random sample of 1,000 genes. Scores from the list of putative actionable conditions (median = 12) and the ACMG list (median = 11) were both statistically different than the randomly selected genes (median = 7) (P < 0.0001, two-tailed Mann-Whitney test). Genet Med 18 5, 467–475. CONCLUSION: Gene–disease pairs having a score of 11 or higher represent the top quintile of actionability. The semiquantitative metric effectively assesses clinical actionability, promotes transparency, and may facilitate assessments of clinical actionability by various groups and in diverse contexts. Genet Med 18 5, 467–475