IN 1989 things seemed so straightforward. Geneticists had just tracked down the gene responsible for cystic fibrosis, and many people must have thought that its discovery would quickly lead to universal screening campaigns to pick up healthy carriers whose children might have the disease. DNA tests are now available for people with a family history of cystic fibrosis but debate continues to rage over whether those tests should be used to screen sections of the general population.
The debate has centred on a range of ethical and economic issues, such as how genetic information might affect the emotional wellbeing of those tested and whether it would be cost-effective to screen entire sections of populations. Now doctors must contend with a further, and rather more practical, complication 鈥� which test to use.
The reason is that research into the molecular structure of the cystic fibrosis gene, called CFTR, has revealed not one mutation and one disease, but many mutations and many diseases, with vastly different symptoms and severities. This variability is a real headache for would-be gene screeners who must decide how many and which mutations to test for. Apply the wrong test and the result could be unfortunate couples falsely reassured that there is no risk that their children will have cystic fibrosis. But getting it right is no easy task. Each of the 400 mutations discovered to date requires its own unique gene probe. So it would be impractical to test for them all.
Advertisement
To make matters worse, no one has yet found a clear link between the type of mutation and the nature and severity of the resulting condition. For decades, a mutation in the CFTR gene had been thought to lead inevitably to the accumulation of suffocatingly thick mucus in the lungs and often severe digestive problems. Now a new class of patients has emerged, people with relatively minor symptoms such as asthma or bronchitis no one had thought were linked to a genetic defect. Even more bizarrely, mutations in the cystic fibrosis gene have also turned up in men who are perfectly healthy 鈥� but infertile because they lack a vas deferens, the tube which carries sperm out of the testicles.
To complicate the picture still more, the assumption that cystic fibrosis affects predominantly 鈥渨hites鈥� is being challenged. Increasingly, American and British doctors are finding that Hispanics, Pakistanis, 鈥渂lacks鈥� and other 鈥渘on-whites鈥� can carry mutations on the CFTR gene and have children affected with the disease. Even among 鈥渨hites鈥� the picture is far more complex than anyone ever imagined. The frequency of individual mutations within the CFTR gene varies greatly across Europe and between different 鈥渨hite鈥� ethnic groups, however these are defined. And these variations have profound implications for gene screening.
In Britain, for example, the vast majority of cystic fibrosis cases, more than 85 per cent, are caused by one of four mutations. Individuals can send a mouthwash sample for screening by post to University Diagnostics in London. The company will test the sample with probes that detect the four common mutations. But what people considering having this test probably don鈥檛 realise is that it can have little predictive value if they are not stereo-typical of the Northern European classification. In parts of southern Europe, as many as 60 mutations account for less than 75 per cent of people with the disease. So Britons with any southern European ancestors, no matter how distant, could easily carry a mutation that is not one of the common four.
In the US, DNA screening tests are usually carried out by competing commercial laboratories. Each lab advertises tests for different numbers of mutations, typically from 6 to 32, and each test is considered appropriate for the general population. The problem is that they may not suit individual communities, says geneticist Fred Gilbert of Cornell University.
Who counts as 鈥渨hite鈥� for the purposes of cystic fibrosis screening is now highly contentious and nowhere more so than in the US, where the federal government recognises five race-ethnicity categories. The 鈥渨hite鈥� category includes people who trace their origins to the 鈥渙riginal peoples鈥� of Europe, North Africa and the Middle East to the Pakistan border. More problematic when assessing who to screen for the cystic fibrosis gene is the Hispanics category which includes people of 鈥淢exican, Puerto Rican, Cuban, Central or South American or other Spanish culture or origin, regardless of race鈥�. Everyone else has to fit into one of the remaining options: American Indian and Alaskan Native, Asian and Pacific Islander, or African-American. Together these 鈥減eople of colour鈥� now account for more than a quarter of all Americans.
Racial muddle
In the US, the American Society of Human Genetics claims that 鈥渃urrent surveys indicate that 85 to 90 per cent of cystic fibrosis carriers in the North American 鈥榳hite鈥� population can be detected by testing for 6 to 12 mutations鈥�. But it also admits that the detection rate of the standard screening test is substantially lower in 鈥渂lacks鈥�, Hispanics and Asians. One recent study carried out in the southwestern US, for instance, discovered that screening tests using 22 different probes detected only 58 per cent of the mutations in the cystic fibrosis gene among Hispanic people with the disease.
This is bad enough, but it gets even worse. As geneticists from Cornell point out, the Hispanic label itself is 鈥渙f limited value in genetic analyses鈥�: it 鈥渞efers neither to race nor to a defined ethnic subgroup鈥� but is rather a 鈥済eographic label鈥�, they wrote in the American Journal of Human Genetics. Umbrella terms such as Asian or Afro-Caribbean that are commonly used in British biomedical circles are equally nonsensical, as Raj Bhopal, professor of epidemiology at the University of Newcastle points out.
Some scientific papers consider both Europeans and people of Indian and Pakistani origin as subcategories of Caucasians 鈥� a category arising from discredited racial theories of the 18th century. Others put people with relatives in modern Pakistan, Bangladesh or India into a separate South Asian category. British forensic geneticists refer to both Caucasians and Afro-Caribbeans as ethnic groups 鈥� apparently adopting the common practice of using ethnicity as a euphemism to avoid talk of race. Meanwhile, their American counterparts talk of European Caucasian, African American and East Asian as races.
This muddle is bad news for carriers of the cystic fibrosis gene. The potential for misinformation is all too real, especially perhaps in the US, where largely unregulated commercial concerns are moving into the burgeoning market for cystic fibrosis testing. Screening programmes run the risk of misleading their clients, who, as the US Institute of Medicine鈥檚 1994 report Assessing Genetic Risks acknowledges, may go away falsely reassured when an 鈥渆thnic misdiagnosis鈥� inspires the use of 鈥渋nappropriate鈥� probes, or seems to rule out any need for testing.
Uncertain ancestry
Patients may suffer too: children with cystic fibrosis may miss out on an early diagnosis because their parents believe that cystic fibrosis is something only 鈥渨hite鈥� children have. In 1993 doctors at the Children鈥檚 Hospital in Birmingham reported an average delay of more than three years in diagnosing cystic fibrosis in several Asian or 鈥渕ixed-race鈥� children, compared to their 鈥渨hite鈥� counterparts. A recent report prepared by the Cystic Fibrosis Trust in Bromley, Kent, has highlighted this neglect.
Genetic diseases stereotyped as 鈥渂lack鈥� or Asian conditions are plagued by similar problems, says Gilbert. For example, scores of different mutations in the haemoglobin genes can produce a family of blood disorders known as the thalassaemias, characterised by mild to severe anaemias. People deemed at risk include those who 鈥渙riginated鈥� from Italy, Greece, the Middle East, the Indian subcontinent, South China, Southeast Asia, and Africa. 鈥淵et even a Celt can have the gene for thalassaemia,鈥� says Helen MacBeth, an anthropologist at Oxford Brookes University.
Sickle-cell disease provides another example. It is an alteration of the oxygen-carrying haemoglobin in the blood that results from inheriting two copies of a DNA sequence typically regarded as a 鈥渂lack鈥� gene. Darleen Powars of the University of Southern California Medical Center in Los Angeles told readers of the Journal of the American Medical Association last year that 鈥淚n urban centres in the United States, nearly 10 per cent of patients with various sickling disorders identify themselves as 鈥榥on-black鈥�.鈥� Today, she says, patients with sickle-cell disease range from individuals with blond hair and blue eyes to those with olive skin and straight dark hair to those with dark skin and curly black hair.
There is no foolproof way of accessing genetic ancestry either. Most 鈥渨hite鈥� Americans now admit to multiple European ancestry, but these family trees typically include only selected branches. Michael Hout, a sociologist at the University of California at Berkeley charts the curious phenomenon of 鈥渉ow 4.5 million Irish immigrants became 40 million Irish Americans鈥�. He finds that 鈥渢he subjective identification with some ethnic groups, notably the Irish and Germans鈥�, far outstrips their natural increase. Other researchers estimate that there are millions of American 鈥渨hites鈥� who either do not acknowledge, or are unaware of, their African ancestry.
In the midst of these continually evolving and contested identities, medical geneticists tread gingerly. Healthcare activists have already noted and condemned the poor provision of NHS services for thalassaemia and sickle-cell disease, compared to 鈥渨hite鈥� genetic diseases such as phenylketonuria. Britain鈥檚 NHS has reacted to this criticism by launching 鈥渆thnic monitoring鈥� of patients in the hope of pinpointing any unequal provision.
The offer of universal screening could well be the best way to avoid such inequities. Already many hospitals in London and Birmingham screen all newborns for both phenylketonuria and sickle-cell disease. Critics talk of 鈥渨asting money鈥� on sickle-cell screening in places considered to be bastions of 鈥渨hiteness鈥� such as Skye or the Isle of Wight, says Elizabeth Anionwu of the Institute of Child Health. But what is the 鈥渕agic cut off point when enough people are at a high enough risk?鈥� she asks. 鈥淣obody鈥檚 got the answer.鈥�