Trajectory of exonic variant discovery in a large clinical population: implications for variant curation.
Genet Med
; 21(6): 1417-1424, 2019 06.
Article
em En
| MEDLINE
| ID: mdl-30449888
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.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Variação Genética
/
Curadoria de Dados
Tipo de estudo:
Diagnostic_studies
Limite:
Adult
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Female
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Humans
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Male
Idioma:
En
Revista:
Genet Med
Assunto da revista:
GENETICA MEDICA
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Estados Unidos