Policy ForumMedicine

The Ultimate Genetic Test

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Science  01 Jun 2012:
Vol. 336, Issue 6085, pp. 1110-1112
DOI: 10.1126/science.1221037

Encoded in the DNA sequence of our individual genome is the genetic program to build, maintain, and adapt all our tissues and their functions. Each human genome contains 200,000 coding elements (exons) and millions of regulatory elements (1) defining complex signaling and regulatory networks.


Compared with the reference sequence generated by the Human Genome Project, any single individual's genome has about four million sequence variations. Although most of these variants are harmless, some cause disease, predispose people to conditions (2), and determine responses to treatments. In general, the impact of genetic variants is disproportionate to their frequency. For example, some genetic diseases in newborns are frequently caused by de novo personal variants, which include large DNA deletions or duplications (35).

Today, a limited number of variants are detected through targeted genetic tests including some newborn screening tests. Some recent sequencing-based tests target a few hundred genes (6). Whole-genome sequencing (WGS) is already a powerful research tool to study the molecular basis of thousands of diseases. In addition, doctors from at least a dozen large, especially university-related, hospitals also use WGS for some of their patients (mostly with idiopathic diseases or refractory cancers) (79) but usually as part of a clinical study because only a few laboratories generate WGS in certified (CLIA) labs. In some cases, these labs have recently performed sequencing of all of the exons and, if unable to find a genetic cause, have turned to WGS. A few doctors have “prescribed” CLIA-performed WGS to better understand a condition or as supporting information to potentially prevent disease or improve health (10). A more effective approach might be to routinely sequence individuals' entire genome once, preferably early in life, and to continue to use this information to make health-care decisions throughout their lifetime.

The Comprehensive Genetic Test

Similar diseases can result from many different genetic changes, including rare family variants and de novo mutations, in one or multiple genes and regulatory regions (11) that affect a molecular pathway. However, a single genetic variant may have a very different impact on health depending on the other genetic variants that exist in the genome (e.g., modifier genes), environmental factors, or a combination of both. This is why many genetic tests targeted to specific parts of genes have limited explanatory value. For example, it is now accepted that complete sequencing of BRCA1 and BRCA2 genes is more informative than targeting only the exons and nearby splicing regions. Sequencing additional tumor suppressor genes may provide even more powerful information about the basis and progression of cancer (12). By extension, sequencing an individual's entire genome and identifying the variants in all coding and regulatory regions is perceived to be critical to untangling complex regulatory interdependencies in cancer and other diseases and to potentially help with disease prevention, diagnosis, and treatment.

Use of WGS would reduce the undiagnosed cases that result from rare or de novo variants in any of thousands of genes. For example, standard tests for cystic fibrosis miss 20% of carriers in some populations (13). Because 50% of individuals with BRCA mutations have no familial association (12), in the absence of family history, a doctor may not even recognize a need for a targeted test. Accurate WGS would also detect adverse reaction to drugs (14) or anesthesia (15) due to various rare variants. Similarly, this may also be used to help ensure healthy offspring via carrier, preimplantation, or prenatal screens. Furthermore, the complete sequence enables more informative and accurate contextual interpretation of detected genetic variants for presymptomatic predispositions to diseases and help with preventive treatments.

The availability of an individual's WGS would provide immediate access to genetic information and its latest interpretation when needed, e.g., the response to clopidogrel as an urgent heart treatment (16). This readiness would maximize disease diagnosis, prevention, and treatment, such as sudden cardiac arrest, while avoiding delays due to serial hypothesis testing.

Instead of handling different types of partial data sets or making decisions without genetic data, once comprehensive and ultimate genetic information provided by WGS is broadly accepted, many health-related industries can standardize their approaches around WGS data. This would eliminate the need for development of targeted genetic tests or companion diagnostics for each of the hundreds of novel drugs. It would facilitate more informative and efficient disease studies, drug development, and clinical trials. WGS should also lower health-care costs as the result of disease prevention and reduced use of many diagnostic techniques and untargeted treatments.

As with other genetic tests, genome sequencing is noninvasive, as it usually requires only a small sample of saliva or blood. After sequencing is completed and the variant data with supporting statistics are stored, an individual's inherited genome can be queried to help answer health questions over a person's lifetime. A computer program could issue an up-to-date report that lists any actionable warnings or recommended actions. These ever-improving analyses and reports could be tailored according to a person's age, prescription drug use, and reproductive or other choices. Many WGS findings might be automatically reported only later in life when they become actionable. In addition, the person's doctor could initiate other disease-, gene-, or pathway-focused queries to address specific medical issues.

WGS is even more informative and more accurate when included as part of a family genomics program in which all members of a family have their genome sequenced (7, 10). Ultimately, the main goal of WGS and genomic medicine is not only to measure personal propensity to a disease but also to determine genome-specific ways of preventing diseases and improving treatments. The overall clinical value is difficult to define today, as WGS has not yet been used over the course of any one life-span, let alone many, full life-spans. However, values for specific applications will soon be measured as thousands of WGS tests are performed. There is a growing number of examples of patients who have already been molecularly diagnosed (7, 17) or successfully treated (8, 18) after the genetic causes of their disease or condition have been discovered by WGS.

Technical Progress and Challenges

Sequencing and analysis of the human genome's six billion base pairs requires extreme accuracy to prevent errors. Current WGS technology, in spite of accuracy of only one false single-nucleotide variation per 500 kbp (19), requires improvements for broad use in clinical applications. Because the human genome is diploid, it is also critical to determine which variants come from which parent (20) in a cost-effective and scalable manner (21). Currently, long haplotypes and some repeat regions are missing, but that and variant calling accuracy is likely to substantially improve in a few years. In the meantime, actionable WGS-detected variants can be validated by confirmatory testing.

To achieve a broad health impact, millions of human genomes will need to be sequenced each year. With current projected improvements in sequencing instruments (22), a rate of over one million WGS tests per year will be reached in this decade. Also, more CLIA-certified WGS labs are coming online. Furthermore, there are continuous cost-efficiency improvements in WGS (23, 24) and, although not achieved yet, for a genome sequence to cost less than $1000 seems a reachable goal (22). Clinical use of WGS will have additional costs related to operation of certified labs; the need to guarantee a higher accuracy (e.g., the need for higher read coverage or variant validation); and the cost of life-long data storage and clinical (re)interpretation.

Genomic knowledge is growing exponentially, fueled by large-scale sequencing projects such as Encode or the Personal Genome Project (25), the thousands of whole human genomes being sequenced around the world (>10,000 completed since 2009 and 30,000 expected this year); the increasingly common attachment of phenotypic information to genotypes; and fast improvements in genome interpretation software.

Concerns and Policies

WGS as an ultimate genetic test could be ordered for many indications (8, 17, 18) or as a “screening” test (10, 26, 27) for disease prevention and all other uses. Thus, it is important to begin developing policies and recommendations to facilitate clinical adoption of WGS (28). Regulatory agencies and leading professional societies must work together to provide technical and interpretive standards and guidelines for WGS to assure sufficient quality and usability of the data needed for various applications. Industry standards for the format and content of genomic variant lists and interpretation reports are also required. Reliable specificity and sensitivity statistics should be established for various types of variants and distinct genomic regions. The medical usefulness of diverse genomic elements needs to be established through translational research.

There are many other questions to consider. Should WGS results be stored as part of medical records? How will patient autonomy and privacy be protected? If WGS is done early in life, who decides which data can be released until a child is old enough to decide? Who pays for WGS, and, if paid directly by patients, under which conditions can they order it directly? How can WGS be made affordable for everybody? It is also important to guard against the overpromise of WGS benefits and to work to prevent unethical and illegal use of our WGS data by others. Thus far, the U.S. Genetic Information Non-discrimination Act of 2008 (GINA) regulates such use in part, but many more public policy questions will need to be addressed by regulatory or legislative action. Both physicians and the public need to be educated about the benefits and limitations of WGS, as patients will play a vital role in WGS adoption.

By its nature, WGS provides foundational medical information which is expected to play a critical role in health management and in improving doctors' decisions in diagnosis and treatment. Today, though, it is important to follow the “first do no harm” maxim. This means constraining WGS reporting to prevent overinterpretation due to limited understanding of the genome (29) but also using WGS instead of less-informative targeted tests whenever feasible. For now, we should treat most WGS reports as indications requiring further investigation and explain this clearly to users who receive this information. In many cases the complete knowledge of inherited genomic variants alone is not sufficient, because it does not take into account the genome-specific impact of environmental and stochastic factors such as noninherited cancer-causing mutations.

The availability of WGS provokes many important social and ethical questions, such as informed consent and access to one's own genetic information. In continuing this debate, we should cherish our personal genome diversity and celebrate the advances in technology and science that are enabling broader adoption of WGS and that may help people live healthier lives.

References and Notes

  1. Volunteers from the general public working together with researchers to advance personal genomics, www.personalgenomes.org/.
  2. Acknowledgments: The author thanks J. Turcotte, B. Peters, K. Raffel, and C. Reid for their help in writing this paper.
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