Significance Associated with Phenotype Score Aids in Variant Prioritization for Exome Sequencing Analysis.
J Mol Diagn
; 26(5): 337-348, 2024 May.
Article
em En
| MEDLINE
| ID: mdl-38360210
ABSTRACT
Several in silico annotation-based methods have been developed to prioritize variants in exome sequencing analysis. This study introduced a novel metric Significance Associated with Phenotypes (SAP) score, which generates a statistical score by comparing an individual's observed phenotypes against existing gene-phenotype associations. To evaluate the SAP score, a retrospective analysis was performed on 219 exomes. Among them, 82 family-based and 35 singleton exomes had at least one disease-causing variant that explained the patient's clinical features. SAP scores were calculated, and the rank of the disease-causing variant was compared with a known method, Exomiser. Using the SAP score, the known causative variant was ranked in the top 10 retained variants for 94% (77 of 82) of the family-based exomes and in first place for 73% of these cases. For singleton exomes, the SAP score analysis ranked the known pathogenic variants within the top 10 for 80% (28 of 35) of cases. The SAP score, which is independent of detected variants, demonstrates comparable performance with Exomiser, which considers both phenotype and variant-level evidence simultaneously. Among 102 cases with negative results or variants of uncertain significance, SAP score analysis revealed two cases with a potential new diagnosis based on rank. The SAP score, a phenotypic quantitative metric, can be used in conjunction with standard variant filtration and annotation to enhance variant prioritization in exome analysis.
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Base de dados:
MEDLINE
Assunto principal:
Testes Genéticos
/
Bases de Dados Genéticas
Tipo de estudo:
Risk_factors_studies
Limite:
Humans
Idioma:
En
Revista:
J Mol Diagn
Assunto da revista:
BIOLOGIA MOLECULAR
Ano de publicação:
2024
Tipo de documento:
Article