Significance Associated with Phenotype Score Aids in Variant Prioritization for Exome Sequencing Analysis.

Creator(s)

Brian Lee
Lily Nasanovsky
Lishuang Shen
Dennis T. Maglinte
Yachen Pan
Xiaowu Gai
Ryan J. Schmidt
Gordana Raca
Jaclyn A. Biegel
Megan Roytman
Paul An
Carol J. Saunders, Children's Mercy HospitalFollow
Emily G. Farrow, Children's Mercy HospitalFollow
Soheil Shams
Jianling Ji

Document Type

Article

Publication Date

5-2024

Identifier

DOI: 10.1016/j.jmoldx.2024.01.009

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.

Journal Title

The Journal of molecular diagnostics : JMD

Volume

26

Issue

5

First Page

337

Last Page

348

MeSH Keywords

Humans; Exome Sequencing; Retrospective Studies; Databases, Genetic; Genetic Testing; Phenotype

Keywords

Exome Sequencing; Retrospective Studies; Genetic Databases; Genetic Testing; Phenotype

Recommended Citation

Lee B, Nasanovsky L, Shen L, et al. Significance Associated with Phenotype Score Aids in Variant Prioritization for Exome Sequencing Analysis. J Mol Diagn. 2024;26(5):337-348. doi:10.1016/j.jmoldx.2024.01.009