ArticleGenetics in medicine : official journal of the American College of Medical Genetics2019
Trajectory of exonic variant discovery in a large clinical population: implications for variant curation.
Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts.American journal of human genetics · 2022Article
- Framework From a Multidisciplinary Approach for Transitioning Variants of Unknown Significance From Clinical Genetic Testing in Kidney Disease to a Definitive Classification.Kidney international reports · 2022Article
- A Genome-First Approach to Characterize DICER1 Pathogenic Variant Prevalence, Penetrance, and Phenotype.JAMA network open · 2021Article
- Future directions for high-throughput splicing assays in precision medicine.Human mutation · 2019Article
- A data-driven evaluation of the size and content of expanded carrier screening panels.Genetics in medicine : official journal of the American College of Medical Genetics · 2019Article
- Predictive value of genomic screening: cross-sectional study of cystic fibrosis in 50,788 electronic health records.NPJ genomic medicine · 2019Article
- Exome-Wide Rare Variant Analysis From the DiscovEHR Study Identifies Novel Candidate Predisposition Genes for Endometrial Cancer.Frontiers in oncology · 2019Article
Corrections and comments
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Authors and funding
7 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
purposePrecision 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.
methodsWe 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.
resultsVariant 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.
conclusionThe 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.
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