Personalized genomic disease risk of volunteers

Proc Natl Acad Sci U S A. 2013 Oct 15;110(42):16957-62. doi: 10.1073/pnas.1315934110. Epub 2013 Sep 30.


Next-generation sequencing (NGS) is commonly used for researching the causes of genetic disorders. However, its usefulness in clinical practice for medical diagnosis is in early development. In this report, we demonstrate the value of NGS for genetic risk assessment and evaluate the limitations and barriers for the adoption of this technology into medical practice. We performed whole exome sequencing (WES) on 81 volunteers, and for each volunteer, we requested personal medical histories, constructed a three-generation pedigree, and required their participation in a comprehensive educational program. We limited our clinical reporting to disease risks based on only rare damaging mutations and known pathogenic variations in genes previously reported to be associated with human disorders. We identified 271 recessive risk alleles (214 genes), 126 dominant risk alleles (101 genes), and 3 X-recessive risk alleles (3 genes). We linked personal disease histories with causative disease genes in 18 volunteers. Furthermore, by incorporating family histories into our genetic analyses, we identified an additional five heritable diseases. Traditional genetic counseling and disease education were provided in verbal and written reports to all volunteers. Our report demonstrates that when genome results are carefully interpreted and integrated with an individual's medical records and pedigree data, NGS is a valuable diagnostic tool for genetic disease risk.

Keywords: disease prediction; molecular medicine; whole exome sequencing.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alleles
  • Female
  • Genes, Dominant / genetics
  • Genes, Recessive / genetics
  • Genetic Counseling*
  • Genetic Diseases, Inborn / diagnosis
  • Genetic Diseases, Inborn / genetics*
  • Humans
  • Male
  • Medical Records*
  • Middle Aged
  • Patient Education as Topic*
  • Pedigree*
  • Risk Factors
  • Sequence Analysis, DNA / methods*