Taxonomizing, sizing, and overcoming the incidentalome

Abstract

Purpose: With the advent of whole-genome sequencing made clinically available, the number of incidental findings is likely to rise. The false-positive incidental findings are of particular clinical concern. We provide estimates on the size of these false-positive findings and classify them into four broad categories.

Methods: Whole-genome sequences (WGS) of nine individuals were scanned with several comprehensive public annotation databases and average estimates for the number of findings. These estimates were then evaluated in the perspective of various sources of false-positive annotation errors.

Results: At present there are four main sources of false-positive incidental findings: erroneous annotations, sequencing error, incorrect penetrance estimates, and multiple hypothesis testing. Of these, the first two are likely to be addressed in the near term. Conservatively, current methods deliver hundreds of false-positive incidental findings per individual.

Conclusion: The burden of false-positives in whole-genome sequence interpretation threatens current capabilities to deliver clinical-grade whole-genome clinical interpretation. A new generation of population studies and retooling of the clinical decision-support approach will be required to overcome this threat.

Figure 1

Overview of the genes with rare or novel nonsynonymous variants at conserved loci. Each row in the heatmap represents a unique transcript—a unique subsequence of the genome obtained during sequencing. The number of variants meeting the criteria of being nonsynonymous, rare, and conserved (see Table 1 for definitions) was used to cluster transcripts and individuals. These numbers ranged from 0 (white) to the maximum of 13 (dark red) as shown in the color bar on the top right. Most variants were unique to each individual genome. Each individual presents an average of 222 such variants (range from 168 to 260) that are shown as red blocks on the heatmap (left). A total of 65 transcripts had more than one variant in all nine genomes. The top part of the heatmap was zoomed in on the right, which reveals that the genes such as HYDIN, PDE4DIP, PRIM2, and SEC22B tend to have more than one rare/novel nonsynonymous variant at a conserved locus, consistently in all genomes analyzed. The identification of these “hypervariable” genes can help to reduce the false-positive findings, but even a residual small false-positive rate (e.g., 1%) will incur a substantial population-wide reporting burden, as described in the text.