Format

Send to

Choose Destination
See comment in PubMed Commons below
PLoS One. 2015 Sep 2;10(9):e0135193. doi: 10.1371/journal.pone.0135193. eCollection 2015.

Identification of Medically Actionable Secondary Findings in the 1000 Genomes.

Author information

  • 1Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri, United States of America.
  • 2Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri, United States of America; Department of Genetics, Washington University School of Medicine, St Louis, Missouri, United States of America.
  • 3Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri, United States of America.
  • 4Department of Neurology, Washington University School of Medicine, St Louis, Missouri, United States of America.
  • 5Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri, United States of America.
  • 6Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St Louis, Missouri, United States of America; Division of Statistical Genomics, Washington University School of Medicine, St Louis, Missouri, United States of America.
  • 7Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri, United States of America; Department of Genetics, Washington University School of Medicine, St Louis, Missouri, United States of America; Chief Informatics Officer, Pierian DX, St Louis, Missouri, United States of America.
  • 8Department of Genetics, Washington University School of Medicine, St Louis, Missouri, United States of America.

Abstract

The American College of Medical Genetics and Genomics (ACMG) recommends that clinical sequencing laboratories return secondary findings in 56 genes associated with medically actionable conditions. Our goal was to apply a systematic, stringent approach consistent with clinical standards to estimate the prevalence of pathogenic variants associated with such conditions using a diverse sequencing reference sample. Candidate variants in the 56 ACMG genes were selected from Phase 1 of the 1000 Genomes dataset, which contains sequencing information on 1,092 unrelated individuals from across the world. These variants were filtered using the Human Gene Mutation Database (HGMD) Professional version and defined parameters, appraised through literature review, and examined by a clinical laboratory specialist and expert physician. Over 70,000 genetic variants were extracted from the 56 genes, and filtering identified 237 variants annotated as disease causing by HGMD Professional. Literature review and expert evaluation determined that 7 of these variants were pathogenic or likely pathogenic. Furthermore, 5 additional truncating variants not listed as disease causing in HGMD Professional were identified as likely pathogenic. These 12 secondary findings are associated with diseases that could inform medical follow-up, including cancer predisposition syndromes, cardiac conditions, and familial hypercholesterolemia. The majority of the identified medically actionable findings were in individuals from the European (5/379) and Americas (4/181) ancestry groups, with fewer findings in Asian (2/286) and African (1/246) ancestry groups. Our results suggest that medically relevant secondary findings can be identified in approximately 1% (12/1092) of individuals in a diverse reference sample. As clinical sequencing laboratories continue to implement the ACMG recommendations, our results highlight that at least a small number of potentially important secondary findings can be selected for return. Our results also confirm that understudied populations will not reap proportionate benefits of genomic medicine, highlighting the need for continued research efforts on genetic diseases in these populations.

PMID:
26332594
PMCID:
PMC4558085
DOI:
10.1371/journal.pone.0135193
[PubMed - indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Public Library of Science Icon for PubMed Central
    Loading ...
    Support Center