High-frequency actionable pathogenic exome variants in an average-risk cohort

Abstract

Exome sequencing is increasingly utilized in both clinical and nonclinical settings, but little is known about its utility in healthy individuals. Most previous studies on this topic have examined a small subset of genes known to be implicated in human disease and/or have used automated pipelines to assess pathogenicity of known variants. To determine the frequency of both medically actionable and nonactionable but medically relevant exome findings in the general population we assessed the exomes of 70 participants who have been extensively characterized over the past several years as part of a longitudinal integrated multiomics profiling study. We analyzed exomes by identifying rare likely pathogenic and pathogenic variants in genes associated with Mendelian disease in the Online Mendelian Inheritance in Man (OMIM) database. We then used American College of Medical Genetics (ACMG) guidelines for the classification of rare sequence variants. Additionally, we assessed pharmacogenetic variants. Twelve out of 70 (17%) participants had medically actionable findings in Mendelian disease genes. Five had phenotypes or family histories associated with their genetic variants. The frequency of actionable variants is higher than that reported in most previous studies and suggests added benefit from utilizing expanded gene lists and manual curation to assess actionable findings. A total of 63 participants (90%) had additional nonactionable findings, including 60 who were found to be carriers for recessive diseases and 21 who have increased Alzheimer's disease risk because of heterozygous or homozygous APOE e4 alleles (18 participants had both). Our results suggest that exome sequencing may have considerably more utility for health management in the general population than previously thought.

Keywords: diabetes mellitus; dilated cardiomyopathy; maturity-onset diabetes of the young.

Figure 1.

(A) Workflow; (B) variant filtering and curation. (A) A high-level overview of the workflow from exome sequencing through variant filtering and curation and reporting. (B) A more detailed description of the variant filtering criteria used to determine which variants would undergo manual curation.

Figure 2.

Actionable and nonactionable exome findings. The percentage of participants in whom each category of finding was identified. These include actionable findings, which are defined as likely pathogenic or pathogenic variants in genes associated with diseases that are moderately to highly penetrant, the identification of which was likely to result in altered medical management in the form of treatment, screening, or preventative measures, as described in published guidelines. The second category of findings represented is carrier status, which includes participants in whom at least one heterozygous likely pathogenic or pathogenic variant was identified in a gene associated with an autosomal recessive condition. The final category of finding is APOE status. The “APOE e4” designation includes all participants who had either one or two e4 alleles.