Clinicians and the public have held great hope for years that genomic analysis would transform the prevention and treatment of disease, but although costs may be plummeting, challenges persist, investigators reported March 12th in JAMA.
Sequencing the genome of individuals has become much less expensive, but translating those results into clinically useful information is labor intensive, and fraught with inconsistencies and uncertainties, reported Dr. Frederick E. Dewey of the Stanford (Calif.) Center for Inherited Cardiovascular Disease and his associates (JAMA 2014;311:1035-44).
Three academic primary care physicians and two academic medical geneticists separately reviewed whole-genome sequencing (WGS) results from 12 adult participants, and each proposed clinical follow-up based on the findings. The DNA from whole-blood samples obtained from five men and seven women without any known inherited disease risk was sequenced by commonly used platforms (all 12 at Illumina, with confirmatory sequencing performed for 9 of the participants by Complete Genomics). Two of the primary care physicians had no previous experience with genomic medicine or genetics training, the investigators reported.
Up to one-fifth of gene variants known to be associated with disease risk were not covered at a minimum threshold for discovery, meaning there could be significant gaps in predicting individual risk. For those genetic variants that met the threshold, concordance between the two sequencing platforms was high for common variants (99%), but was substantially lower for genetic variants that were candidates for inherited disease risk (median, 33%; range, 10%-75%), Dr. Dewey and his associates said.
For each participant, the WGS identified between 90 and 127 novel or rare genetic variations, and between 12 and 20 commonly reported variations, all candidates for curation with respect to personal risk and carrier status for inherited disease. The geneticists’ review of the evidence for pathogenicity for each variant required a median time of 54 minutes (range, 5-223 minutes). Based on this finding, investigators estimated the median cost for sequencing and variant interpretation for each participant was $14,815.
Review of the medical genomics report by the three primary care physicians prompted consideration of a median one to three initial follow-up referrals and diagnostic tests per participant. The agreement between physicians about suitability for follow-up of findings was fair, the investigators reported.
In the end, 1 of the 12 participants went on to take action as a result of the findings. A BRCA1 mutation was found in a woman with no family history of breast or ovarian cancer, and she subsequently underwent prophylactic bilateral salpingo-oophorectomy.
Overall, the results illustrate several challenges to clinical adoption of whole-genome sequencing, the authors suggested. Although the analytical validity of WGS is improving, technical challenges to sensitive and accurate assessment of individual genetic variation remain. The finding of only one-third of insertion/deletion genetic variants in inherited disease genes confirmed by the second sequencing platform suggests that variants likely to be pathogenic are more often inconsistently identified, Dr. Dewey and his associates said.
"In this exploratory study of 12 volunteer adults, the use of WGS was associated with incomplete coverage of inherited disease genes, low reproducibility of genetic variation with the highest potential clinical effects, and uncertainty about clinically reportable findings," they wrote.
The research was supported by grants from the National Institutes of Health, the Breetwor Family Foundation, and the LeDucq Foundation. Dr. Dewey reported being a stockholder and member of the scientific advisory board of Personalis, a privately held genome interpretation company, and receiving royalties for patented technology related to genome sequencing. Some of his associates were scientific advisers for companies involved in genomics or received royalties for patented technologies related to genome sequencing.
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