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Updated: Feb 2, 2026
07:15
Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
Published on: January 16, 2019
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High-frequency actionable pathogenic exome variants in an average-risk cohort.
Shannon Rego1, Orit Dagan-Rosenfeld1, Wenyu Zhou1
1Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA.
Cold Spring Harbor Molecular Case Studies
|November 30, 2018
Summary
Exome sequencing in healthy individuals reveals significant medical insights. A substantial portion had actionable genetic findings and carrier statuses, suggesting broader utility for health management.
Area of Science:
- Genomics
- Personalized Medicine
- Population Health
Background:
- Exome sequencing is growing in clinical use, but its value in healthy populations is understudied.
- Previous research often focused on limited gene sets and automated variant analysis.
Purpose of the Study:
- To determine the frequency of medically actionable and relevant exome findings in a general population sample.
- To evaluate the utility of exome sequencing for health management in healthy individuals.
Main Methods:
- Analyzed exomes from 70 extensively characterized participants in a longitudinal multiomics study.
- Identified rare pathogenic variants in Mendelian disease genes (OMIM) using ACMG guidelines.
- Assessed pharmacogenetic variants and APOE e4 allele status.
Main Results:
- 17% of participants had medically actionable findings in Mendelian disease genes.
- 90% had nonactionable but medically relevant findings, including recessive disease carrier status (68%) and increased Alzheimer's risk (30%).
- Actionable variant frequency exceeded prior studies, highlighting benefits of expanded gene lists and manual curation.
Conclusions:
- Exome sequencing offers considerable utility for health management in the general population.
- Findings support the value of comprehensive exome analysis beyond targeted gene panels.
- Individualized genetic information can inform proactive health strategies.
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