Clinical Interpretation and Implications of Whole-Genome Sequencing

Study Questions:

What is the current role of whole-genome sequencing (WGS) in clinical medicine?


This was an exploratory study of 12 adult participants who underwent WGS between November 2011 and March 2012. A multidisciplinary team reviewed all potentially reportable genetic findings and five physicians proposed initial clinical follow-up based on the genetic findings. Outcomes included genome coverage and sequencing platform concordance in different categories of genetic disease risk, person-hours spent curating candidate disease-risk variants, interpretation agreement between trained curators and disease genetics databases, burden of inherited disease risk and pharmacogenomic findings, and burden and inter-rater agreement of proposed clinical follow-up.


Approximately 10%-19% of inherited disease genes were not covered to accepted standards for SNP discovery. Genotype concordance was high for previously described single-nucleotide polymorphisms (99%-100%), but low for small insertion/deletion variants (53%-59%). Curation of 90-127 genetic variants in each participant required a median of 54 minutes (range, 5-223 minutes) per genetic variant, resulted in moderate classification agreement between professionals, and reclassified 69% of genetic variants cataloged as disease causing in mutation databases to variants of uncertain or lesser significance. Two to six personal disease-risk findings were discovered in each participant, including one frameshift deletion in the BRCA1 gene implicated in hereditary breast and ovarian cancer. Physician review of sequencing findings prompted consideration of a median of 1-3 initial diagnostic tests and referrals per participant, with fair inter-rater agreement about the suitability of WGS findings for clinical follow-up (Fleiss κ, 0.24; p < 0.001).


The authors concluded that use of WGS was associated with incomplete coverage of inherited disease genes, low reproducibility of detection of genetic variation with the highest potential clinical effects, and uncertainty about clinically reportable findings. In certain cases, WGS will identify clinically actionable genetic variants warranting early medical intervention. These issues should be considered when determining the role of WGS in clinical medicine.


There have been rapid technologic advances over the past several years in the ability to detect genetic variation in humans. While it is now feasible to perform sequencing of the entire genome in individuals, the clinical utility remains unclear as the technology may have surpassed our capacity to interpret the vast information in a meaningful way. This paper demonstrates promise of WGS, but also indicates that much is to be learned before widespread application of this technology.

Keywords: Sequence Analysis, DNA, Genetic Therapy, Diagnostic Tests, Routine, Early Medical Intervention, Cardiology, Genes, BRCA1, Mutagenesis, Insertional, Pregnancy, Prolonged, Cost of Illness, Ovarian Neoplasms

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