Estimating diagnostic noise in panel-based genomic analysis.
Genet Med
; 24(10): 2042-2050, 2022 10.
Article
em En
| MEDLINE
| ID: mdl-35920826
ABSTRACT
PURPOSE:
Gene panels with a series of strict variant filtering rules are often used for clinical analysis of exomes and genomes. Panel sizes vary, affecting the test's sensitivity and specificity. We investigated the background rate of candidate variants in a population setting using gene panels developed to diagnose a range of heterogeneous monogenic diseases.METHODS:
We used the Gene2Phenotype database with the Variant Effect Predictor plugin to identify rare nonsynonymous variants in exome sequence data from 200,643 individuals in UK Biobank. We evaluated 5 clinically curated gene panels of varying sizes (50-1700 genes).RESULTS:
Bigger gene panels resulted in more prioritized variants, varying from an average of approximately 0.3 to 3.5 variants per person. The number of individuals with prioritized variants varied linearly with coding sequence length for monoallelic genes (â¼300 individuals per 1000 base pairs) and quadratically for biallelic genes, with notable outliers.CONCLUSION:
Although large gene panels may be the best strategy to maximize diagnostic yield in genetically heterogeneous diseases, they frequently prioritize likely benign variants requiring follow up. Most individuals have ≥1 rare nonsynonymous variant in panels containing >500 disease genes. Extreme caution should be applied when interpreting candidate variants, particularly in the absence of relevant phenotypes.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Genômica
/
Exoma
Tipo de estudo:
Diagnostic_studies
Limite:
Humans
Idioma:
En
Revista:
Genet Med
Assunto da revista:
GENETICA MEDICA
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Reino Unido