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Genet Med. 2019 Jun;21(6):1417-1424. doi: 10.1038/s41436-018-0353-5. Epub 2018 Nov 19.

Trajectory of exonic variant discovery in a large clinical population: implications for variant curation.

Author information

1
Geisinger Clinic, Geisinger Health System, Danville, PA, USA. umirshahi1@geisinger.edu.
2
Geisinger Clinic, Geisinger Health System, Danville, PA, USA.

Abstract

PURPOSE:

Precision health initiatives and reduced sequencing costs are driving large-scale human genome analyses. Genetic variant curation is a bottleneck in clinical applications. The burden of variant curation can be high for newly discovered variants because they are less likely to have undergone previous clinical annotation; the rate of discovery of genetic variants in large clinical populations has not been empirically determined.

METHODS:

We determined the rate of accrual of unique sequence variants in 90,000 exome sequences. Separate analyses were done for 17,267 autosomal genes and a subset of 74 actionable genes; the effect of relatedness in the cohort was also determined.

RESULTS:

Variant discovery showed a nonlinear growth pattern. The rate of unique variant accrual decreased as the database size increased; by 90,000 exomes 97% of all projected coding and splicing variants had been observed. Variants in 74 actionable genes showed a similar pattern. Family relatedness slightly reduced the rate of discovery of unique variants.

CONCLUSION:

The heaviest burden of interpretation for genetic variants occurs early and diminishes as the database size increases. Our data provide a framework for scaling pathogenic genetic variant discovery and curation, a critical element of patient care in the era of precision health.

KEYWORDS:

exome sequencing; genomic screening; secondary findings; sequence scaling; variant curation

PMID:
30449888
DOI:
10.1038/s41436-018-0353-5

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