Uncertainty is a problem for clinical whole genome sequencing

12 March 2014

Challenges to the implementation of whole genome sequencing (WGS) in health services have been underlined by a US trial.
The purpose of the research was to evaluate the process of clinical whole genome sequencing, particularly the identification of clinically relevant genetic variants, the resources required, and the clinical actions indicated. Twelve healthy adult men and women received WGS using both Illumina and Complete Genomics sequencing platforms between 2011 and 2012.
It was found that 10-19% of known ACMG-reportable inherited disease genes were not sequenced to the standards required for variant discovery, and for some sorts of genetic variants (including clinically relevant ones) results were quite variable between the different sequencing platforms.
Expert analysis of 90-127 genetic variants of potential interest in each patient typically took about an hour per variant, and the experts did not always agree on the conclusions drawn about each one. Overall, between two and six disease-risk associated genetic variants were identified in each participant, including one BRCA1 gene mutation associated with hereditary breast and ovarian cancer syndrome.
On the positive side, the costs of clinical WGS were found to be relatively modest at around $15,000 per patient, with average follow-up costs (clinical tests suggested on the basis of genomic findings) of between $351 and $776 per patient. Given that this included analysis and expert interpretation as well as WGS, these figures were lower than might have been expected.
Overall, the researchers concluded that ‘human resource needs for full clinical interpretation of WGS data remain considerable, and much uncertainty remains in classification of potentially pathogenic genetic variants’.  This is an obvious problem for the implementation of widespread clinical WGS; not enough is yet known about disease-associated genetic variants to allow rapid or straightforward conclusions about clinical significance. This is a problem that will only be solved by amassing a sufficiently large body of high quality sequence and medical data.
Meanwhile, as an editorial accompanying the research paper notes, it is open to question whether WGS data for a patient ‘will decrease uncertainty and improve outcomes or merely exponentially increase the complexity of clinical care’.

However, it is worth noting that from only twelve participants, one woman received highly significant medical information; the BRCA1 mutation was confirmed by diagnostic testing and she opted for prophylactic removal of her ovaries to prevent possible ovarian cancer and frequent monitoring for breast cancer. As this woman did not have a family history that would have suggested a high cancer risk, the clinical WGS had a significant health impact.