The deeper we dive into the post-genomic era, the murkier appear the issues surrounding genetic testing and its role in medicine. For deadly diseases with clear causation and effective treatments, the question of whether to pursue predictive testing or not has an obvious answer. More often, as in the case of ApoE alleles and Alzheimer disease, genes confer risk but do not spell destiny (see recent live discussion on the topic of ApoE testing). Or, in the case of the presenilin or APP mutations that cause early onset familial AD, the genetic causality is clear, but there is no way yet to prevent or cure the disease (see essay on genetic testing for these diseases). In these situations, the question of whether physicians recommend genetic testing, or patients or their families choose it, becomes fraught with uncertainty and ethical questions.

How to balance, or even measure, the benefits versus potential harm of genetic testing in different clinical scenarios is an area of active debate among geneticists, ethicists, clinicians, and patients. Two articles out this week address aspects of the issue. One looks at the results of carrier testing for Gaucher disease. The other discusses “personal genomics,” a trend that is set to take hold in the next few years as whole-genome sequencing becomes a reality for more people. That article lays out future challenges that will confront the health care system as more and more people gain access to the entirety of their genetic endowment, for better or worse.

Gaucher disease (GD) is an autosomal-recessive lysosomal storage disorder caused by mutations in the glucocerebrosidase gene. The mutations occur with higher frequency among Ashkenazi Jews, and GD is included in a panel of genetic tests offered to prospective parents in this group. (The panel includes Tay-Sachs disease and 12 other conditions that occur with an elevated frequency in this group.) However, unlike Tay-Sachs, which is rare and invariably fatal early in life, mutations associated with GD are quite common, and have a low penetrance. Some widespread mutations can cause a range of conditions, from asymptomatic decreases in enzyme activity to severe disease, making counseling of carriers a complex task. In addition, the disease is treatable with glucocerebrosidase replacement therapy, albeit at great expense. For these reasons many physicians’ organizations counsel against testing for GD, but the test is widely offered in the U.S. and Israel.

In a study published this week in JAMA, Ephrat Levy-Lahad and colleagues at the Shaare Zedek Medical Center in Jerusalem examined the use and outcomes of screening for GD mutations among couples and women who were pregnant or planning to get pregnant as a model for what to expect as use of screening for low-penetrance, less serious, or treatable diseases increases. Screening was common: the investigators found nearly 29,000 people who were screened at Israeli genetic centers between 1995 and 2003, with 5.7 percent discovered to carry a GD mutation. Of those, there were 83 couples where both partners carried a GD allele, and 65 of them became pregnant. Three-quarters of their fetuses were tested, and one-quarter proved to have inherited mutated alleles from both parents. Most of those (85 percent) had type 1 mutations, which predict asymptomatic or mildly affected offspring.

Led by first author Shachar Zuckerman, the researchers then looked at what parents did with this information. They found that most couples chose to continue their pregnancy if they discovered type 1 GD. However, of 13 in this class, two chose termination, raising the possibility that some terminated pregnancies might have produced healthy children with few or no symptoms of the disease. Of people who received additional medical counseling, none terminated their pregnancy because of type 1 mutations. Two of three couples for whom genetic profiling predicted moderate disease chose termination.

How useful, then, is GD carrier testing? The stated goal of carrier screening is to reduce the burden of genetic diseases, but in this case, knowing the genetic status of the fetus resulted in relatively few terminations. The clinical application of the genetic information was limited, and the authors concluded, “The main possible benefit was providing couples with knowledge and control.” The results are likely to be repeated as genetic testing increases for other relatively mild, low penetrance, or treatable diseases, where the mere availability of a test can be a driving force for its introduction, the authors write.

In an accompanying editorial, Ernest Beutler of the Scripps Research Institute in La Jolla, California, goes further. He opines that until clinicians understand why the same mutation can lead to severe disease in one person or none at all in another, “Screening for Gaucher disease will likely do more harm than good.”

In a separate wrinkle to the GD story, a new study by Lorraine Clark and colleagues at Columbia University in New York fuels existing suspicion that mutations in the glucocerebrosidase gene may confer susceptibility to Parkinson disease, and modify age at onset (see PDGene). The paper appeared in the September 18 issue of Neurology. Thus, carrier testing for GD may bring parents-to-be additional, complex, and possibly unwanted information about their own future health risks (for an expert view on the current status of genetic testing for PD, see Klein and Schlossmacher, 2006).

As complicated as these issues are, they concern a single gene, and in this sense represent but the tip of the iceberg in dealing with the genetic information that is coming with the next development in genetic screening, that is, the personal genome. With both James Watson and Craig Venter in possession of their own complete genetic codes, the stage is set for more people to read the books of their lives. What will be the challenges to the medical system of having this much information? Amy McGuire of Baylor College of Medicine in Houston, Texas, and three other medical ethicists consider this question in a policy forum in today’s issue of Science.

“We currently face an inflection point in clinical medicine as we move from specific diagnostic tests for particular disorders to much broader assays for variants whose effects we do not yet fully understand,” they write. “The medical community needs to consider the ways in which routine generation of this information will affect our health system.”

For example, McGuire and colleagues cite the case of recent association studies that link coronary heart disease to a common gene variant on chromosome 9. The actual increase in risk is tiny, and while these studies offer insight into disease mechanisms, no one is rushing to test people in the clinic for the presence of the variant.

Nonetheless, the potential for clinical application of personal genomic information is great, according to McGuire and colleagues, provided it is handled properly. “Successful integration of personal genomics into routine clinical care will require clear standards, multidisciplinary collaboration, and careful consideration of the ethical, social, and clinical implications,” they write. The authors call for more training for doctors in the value, and limitations, of genetic information, and how to pass that information on to their patients. Also needed will be clear guidelines on which tests are clinically relevant. These authors foresee difficult questions of cost, access, and social justice that will arise when inequalities in health care afford some people but not others the opportunity to get a look at one’s own genome.—Pat McCaffrey


No Available Comments

Make a Comment

To make a comment you must login or register.


Webinar Citations

  1. Susceptibility Testing and Risk Assessment in Alzheimer Disease

Paper Citations

  1. . The genetics of Parkinson disease: Implications for neurological care. Nat Clin Pract Neurol. 2006 Mar;2(3):136-46. PubMed.

Other Citations

  1. essay on genetic testing

External Citations

  1. PDGene

Further Reading

No Available Further Reading

Primary Papers

  1. . Carrier screening for Gaucher disease: lessons for low-penetrance, treatable diseases. JAMA. 2007 Sep 19;298(11):1281-90. PubMed.
  2. . Medicine. The future of personal genomics. Science. 2007 Sep 21;317(5845):1687. PubMed.
  3. . Carrier screening for Gaucher disease: more harm than good?. JAMA. 2007 Sep 19;298(11):1329-31. PubMed.
  4. . Mutations in the glucocerebrosidase gene are associated with early-onset Parkinson disease. Neurology. 2007 Sep 18;69(12):1270-7. PubMed.