A Genetic Checkup: Lessons from Huntington Disease and Cystic Fibrosis

Thom Graves Media While genome sequencing may be the new kid on the block--perhaps now with a cracking voice and fuzzy facial hair--predicting phenotypes is the stuff of classical genetics, honed on the rare single-gene disorders, such as Huntington disease (HD) and cystic fibrosis (CF), which dominated the field in the last century (see Genetic Testing Timeline). "Geneticists today are portrayed as soothsayers of the future. But predictive medicine and testing has a significant history," says Michael Hayden, professor of medical genetics at the University of British Columbia. To date, predictive medicine has informed would-be parents of risks to their children, or presaged adult-onset conditions, such as HD or BRCA1 breast cancer. But with testing outpacing treatment, genetic screening has sometimes done little more than satisfy curiosity. While new studies indicate a value in knowing the details, there can be a price to pay for genetic fortune-telling: stigma and the fear of lost jobs or health benefits. Consequently, the percentage of people offered tests who actually take them (termed "uptake") has not been extensive. In some countries, such as Scotland and Canada, however, predictive testing for single-gene disorders has had very promising results, providing guidelines for channeling the genetic information avalanche into clinical practice. The bench-to-bedside saga of HD serves as a model for the predictive medicine to come. "HD has been predictable longer than any other single-gene disorder, and it is therefore where we have the most experience in predictive testing," says Hayden, whose group tracks HD testing in Canada.1 CF screening, which has received somewhat more acceptance, also provides valuable insights. GENETIC TESTING IN CONTEXT HD is straightforward in a scientific sense: The disease is severe and untreatable, and the mutation is invariably an expanding triplet repeat. In contrast, CF symptoms vary; some are controllable, and treatments are on the horizon. Yet, the more than 1,000 known mutations in the CFTR gene complicate testing. One widely used 25-mutation CF panel, for example, detects 90% of Caucasian carriers, 97% of Ashkenazi Jewish carriers, but only 69% and 57% of African-Americans and Hispanics, respectively. Expanded panels of mutations geared to specific populations considerably enhance the test's power. In the 1970s, population-based screens to detect carriers of Tay-Sachs disease and sickle cell disease identified couples who had a 25% chance of passing on either disorder to offspring, enabling them to make informed reproductive decisions. Like most recessive disorders, symptoms of these conditions begin in infancy. HD is different. Like most dominant disorders, symptoms begin in adulthood. And so a test on an adult predicts that person's future, rather than providing risk figures for offspring--a whole different psychological ballgame. GENETIC TESTING IN THE DEVELOPING WORLD It didn't take unraveling the human genome sequence to reveal the effects of recessive genetic disorders in many nations; inbreeding did that years ago. Articles in genetics journals have long reported increased prevalence of recessive disorders in parts of Africa, the Middle East, and India, where 20%-50% of marriages are consanguineous. Despite these pockets of genetic uniformity and the otherwise rare, single-gene disorders that they illuminate, the number-one killer in the developing world is infectious disease. In Africa, 63% of deaths are due to communicable diseases, compared to just 8% in Europe, said Alan Bittles, director of the Centre for Human Genetics at Edith Cowan University, Perth, Australia, at the 19th International Congress of Human Genetics in Melbourne. "Do we really have to worry about genetic diseases in the less developed countries? Shouldn't we concentrate on infectious disease?" Despite the relative rarity of genetic disease in the developing world, the sheer number of people there, 81% of the global population, translates into many with inherited illness, and that can facilitate the spread of infection. Just as people with HIV reintroduced tuberculosis, those whose inherited disease increases their susceptibility to infectious disease could do the same in the developed world, home to many pathogens. "Thirty to 80% of thalassemia major patients worldwide have hepatitis B or C. Underlying genetic defects, when intimately associated with a weakened population, cause infectious diseases to be more prevalent," Bittles said. Most data on predictive testing come from countries where the government is scientifically informed and supportive. Not all are this way. "In the US, people are very worried about health insurance and whether discrimination could result from any test," says Robert Williamson, professor of medical genetics at the University of Melbourne. Francis Collins, director of the National Human Genome Research Institute in the United States, has long promoted legislation against genetic discrimination. "We don't want the public to recoil from genetic information," he said at the 19th International Congress of Human Genetics in Melbourne in July 2003. Before genome fame, Collins led one of the teams that discovered the CF gene.2 THE HD EXPERIENCE Progress in genetic testing means sharpening predictions. HD has taught researchers that this happens gradually. Before any HD test existed, a person "at-risk" (having an affected parent) faced a 50% chance of suffering the same fate. With discovery in 1983 of the HD marker near the causative gene on chromosome 4, an at-risk person whose relatives took the test could know with more than 96% certainty.3 The gene's discovery itself a decade later raised the predictive power to near 100%.4 Today, neuroimaging can spot telltale shrinking of certain brain structures that precedes symptoms by years, and the number of triplet repeats correlates to age of symptom onset. "The question for people at-risk has changed from 'Will I get HD?' to 'When will I get HD?' One can now predict with relative certainty when they are likely to manifest symptoms," says Hayden. That newfound certainty frightens people. Many who had indicated before 1983 that they would take a predictive test when it became possible did not do so. The Canadian analysis found an uptake of about 18%; Hayden extrapolates that 50% to 70% of at-risk individuals did not follow through when the hypothetical test became reality. Attitudes in Australia are similar. "While only about 25% of those at-risk have taken the test, fully 100% say that they are pleased that the test is available," says Williamson. In the United States, uptake is about 5%, says neurology professor Richard Myers, Boston University School of Medicine. "HD testing is by far the most widely used genetic test in the US, with more than 300 presymptomatic tests performed each year. But we don't document them the way the Canadians do, because many people pay out-of-pocket and are very private." In the Canadian study, more surprising than low uptake was who took the test; it was not predominantly the youngest adults seeking information for starting families, as many researchers expected. Most of the 1,061 tested individuals were between 30 and 40 years old. Only 70 people were older than 60 years, and the oldest was 95. "The most common reason for testing was to resolve uncertainty and plan for the future, careers, and retirement. People wanted to know whether they would need to hire a nurse or could afford to purchase a motor home." says Hayden. The Canadian group also has studied psychological reactions five years after predictive testing.5 The news is encouraging. "Even those who learned that they had an increased risk resolved the uncertainty, and that improved their well-being, lowered their anxiety, and decreased depression," explains Hayden. The frequency of suicide attempts did not increase after predictive testing, and maybe even decreased. Other risk factors, such as unemployment, onset of symptoms, and history of psychiatric illness were more highly correlated to suicide attempts than to previous testing for HD. But the study has caveats. People likely to respond poorly may have self-selected out of testing, and participants received extensive genetic counseling before and after testing. All of these factors affect uptake. THE CF STORY Testing for CF differs because it identifies carriers and screens entire populations, rather than only affected families. Like HD testing, demand for CF testing has grown gradually, and it can bring the relief of knowing one's fate. Williamson and colleagues screened 15,000 people for CF in North London from 1990 to 1993.6 "We identified 600 to 700 carriers, and offering screening did not result in any anxiety," Williamson recalls. Most participants were young adults, but many were over 40 and just curious. The key finding was the importance of the setting in test acceptance. "In the east of Scotland, about two-thirds of pregnant couples come for the test. It is free and offered as part of antenatal care, in the context of a national health service and an antidiscrimination legal position," he relates. CF testing in the United States sprinted ahead to a five-fold increase when the National Institutes of Health, the American College of Medical Genetics, and the American College of Obstetricians and Gynecologists issued a joint statement declaring carrier testing before or during pregnancy a "standard of care."7 "When a test becomes a standard of care, it reduces the stigma," says Mara Aspinall, president of Genzyme Genetics in Framingham, Mass. Regional manager Vivian Weinblatt, a former president of the National Society of Genetic Counselors, initiated the study of nearly 11,000 patients that revealed the increase in uptake, and presented the results at the organization's annual meeting in September. WHERE ASSOCIATION STUDIES FIT Future genetic tests will target common multifactorial disorders, consequently introducing an unsettling uncertainty compared to testing for single-gene disorders. At the heart of the new approach is the association study, which hunts for haplotypes defined by single nucleotide polymorphism patterns, which people with the same disorder share. Each SNP contributes to the risk, along with environmental factors, and that's hard to assess, let alone use as a clinical crystal ball. "There's a distinction between using gene-disease associations to understand pathology and etiology, and looking at the same associations as a tool to institute population screening test programs," says Martin Bobrow, chair of medical genetics at the University of Cambridge. Joel Hirschhorn, director of endocrine genetics at the Massachusetts Institute of Technology Center for Genome Research, contends that a "desk drawer phenomenon" of underreporting negative associations may inflate some study results.8 He surveyed 600 disease associations of common gene variants, and found that of 166 investigated three or more times, the association held up in only six.9 Margaret Wallace, a professor of molecular genetics and microbiology at the University of Florida, Gainesville, predicts: "It will be a while before association study-based data are widely used for genetic counseling for complex disorders, because many studies disagree about linkage and/or the level of increase in risk. It would be nice to have several large studies agree in outcome." But even when the association data becomes robust enough to reliably reveal which individuals can improve their health by changing environmental risk factors, clinical utility remains in question. "Advice not to smoke has generally failed," Collins said at the conference. And identifying a genetic susceptibility simply may not add much to a treatment plan. "Merely knowing that your risk of a heart attack goes from 1-in-4 to 1-in-3 is of no great value if the outcome is to be prescribed the same statin," points out Williamson. Another barrier is the difficulty of convincing healthy people to take a test that will predict illness, especially when treatment is lacking. Bobrow sums up the feeling that widespread genetic testing still lies largely in the future. "Good things can come out of predictive testing. We've learned a lot from the monogenic disorders, and most of that leaves me cautious--not a feeling of impending doom, but a natural caution." Ricki Lewis (rickilewis@nasw.org) is a freelance writer in Scotia, NY. References 1. H. Hogg et al., "Predictive, pre-natal and diagnostic genetic testing for Huntington's disease: the experience in Canada from 1987-2000," Clin Genet, 63:462-75, June 2003. 2. J.R. Riordan et al., "Identification of the cystic fibrosis gene: cloning to characterization of complementary DNA," Science, 245:1066-73, 1989. 3. J.F. Gusella et al., "A polymorphic DNA marker genetically linked to Huntington's disease," Nature, 306:234-8, 1983. 4. Huntington's disease collaborative research group, "A novel gene containing a tri-nucleotide repeat that is expanded and unstable on Huntington's disease chromosomes," Cell, 72:971-83, 1993. 5. E.W. Almquist et al., "Psychological consequences and predictors of adverse events in the first 5 years after predictive testing for Huntington's disease," Clin Genet, 64:300-9, October 2003. 6. R. Williamson, "Universal community carrier screening programme for cystic fibrosis," Nat Genet, 3:195-201, 1993. 7. W.W. Grody et al., "Laboratory standards and guidelines for population-based cystic fibrosis carrier screening," Genet Med, 3:149-54, 2001. 8. K.E. Lohmueller et al., "Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease," Nat Genet, 33:177-82, 2003. 9. J. Hirschhorn, "A comprehensive review of genetic association studies," Genet Med, 4:45-61, 2002. function sendData() { document.frm.pathName.value = location.pathname; result = false if (document.frm.score[0].checked) result = true; if (document.frm.score[1].checked) result = true; if (document.frm.score[2].checked) result = true; if (document.frm.score[3].checked) result = true; if (document.frm.score[4].checked) result = true; if (!result) alert("Please select") return result; } .myradio{background-color : #94bee5} Please indicate on a 1 - 5 scale how strongly you would recommend this article to your colleagues? Not recommended 1 2 3 4 5 Highly recommended Please register your vote

A Genetic Checkup: Lessons from Huntington Disease and Cystic Fibrosis

Interested in reading more?

Become a Member of