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

Cold Spring Harb Mol Case Stud. 2018 Dec 17;4(6):a003178. doi: 10.1101/mcs.a003178. Print 2018 Dec.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alleles
  • Cohort Studies
  • Databases, Genetic
  • Exome / genetics
  • Exome Sequencing / ethics*
  • Exome Sequencing / methods
  • Exome Sequencing / trends*
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease / genetics
  • Genetic Testing / methods
  • Genetic Variation / genetics
  • Genomics
  • Genotype
  • Healthy Volunteers
  • Humans
  • Incidental Findings*
  • Male
  • Phenotype
  • White People / genetics