Even though most direct-to-consumer companies are still offering personal genome testing on the basis of genome-wide scans, it is clear that this technique will be outdated as soon as whole genome sequencing becomes affordable to consumers. Standard genome-wide scans will increasingly fail to cover the latest variants for the prediction of complex diseases when whole genome sequencing is used for variant discovery, and they do not cover variants for monogenic traits. Whole genome sequencing covers the entire DNA sequence, which means that all DNA variations can be read including common and rare variants implicated in monogenic and complex outcomes.
For monogenic diseases, whole genome sequencing will have the same predictive ability as tests of known mutations that are currently conducted in the clinical genetics practice. Whole genome sequencing can simultaneously test for many monogenic diseases, which increases the likelihood that individuals might benefit from knowing their DNA for at least one disease. This feature of whole genome sequencing certainly contributes to a strong sense of personal utility. However, in the absence of a positive family history or early symptoms, the a priori probability of carrying a known mutation will be low. At the same time, whole genome sequencing will also reveal numerous mutations with unknown impact that have never been seen before. These unknown mutations are difficult to interpret. High-throughput algorithms that combine information from biology, bioinformatics, proteomics and population genetics might be developed in the future to predict the effect of the many variants encountered, but at present one needs family, epidemiological or functional studies to quantify the deleterious effect of such mutations.
For complex diseases, whole genome sequencing will also certainly outperform prediction based on genome-wide scans, because more variants are captured. Yet, because complex diseases are only partly determined by genetic variants or are genetically too complex, it should not be expected that prediction of complex diseases becomes markedly better. When the predictive ability remains limited and prevention is effective even in the absence of a genetically increased risk, the likelihood that test results will lead to any benefit or intelligible decisions at the a personal level, is very low.
Does this mean that whole genome sequencing will have no utility at all? This is clearly not the case. There are many tests in health care that have moderate predictive ability for the individual, but these are found useful to make decisions about prevention or treatment for larger groups of people. Similarly, there will be numerous opportunities in health care in which whole genome sequencing likely may be implemented to improve health outcomes in patients and populations; opportunities where a moderate predictive ability is sufficient and the expected benefits are higher. Moderate predictive ability may be sufficient in population-based screening programs, such as breast cancer mammography screening, where whole genome sequencing could be used to differentiate in starting age or frequency of monitoring [17
]. Expected benefits may be larger when tests are targeted to specific at-risk populations, e.g., to identify the genetic cause of congenital disorders in newborns, to search and subsequently test private mutations in families with a positive history of hereditary disease, or to test predisposition to specific drug responses upon indication of symptoms.
Undoubtedly, whole genome sequencing will be implemented in health care when it leads to better health outcomes for populations, even if at the personal level the benefits are modest and many individuals receive a wrong or unnecessary preventive or therapeutic intervention. Health care payers will finance predictive tests that benefit populations at large, but it is unlikely that individual consumers will massively spend money on expensive tests that have moderate predictive ability and unclear personal benefits.