B io Factsheet
Genetic Testing and Screening
This Factsheet: • explains how genetic testing and screening are carried out • summarises the ethical issues associated with testing and screening • provides examples of the types of exam questions that have come up in recent years Strictly speaking, genetic testing is used with individuals who, perhaps because of their family background, believe that they, their children or future children may be at risk of carrying the gene for a genetic disease. Genetic screening involves wider scale testing of populations to determine those individuals that are at risk of a genetic disease. However in the exam, most questions treat testing and screening as the same thing. Be careful though and read the question carefully! Genetic testing can be used to predict the likelihood that an individual will suffer from a genetic disease. Testing can be done: 1. Pre-implantation e.g. by Preimplantation Genetic Diagnosis 2. Pre-natally, e.g. by amniocentesis on 35+ women to test the fetus for Down’s Syndrome 3. On new-born babies 4. On children, for diseases that may become a problem later in life, and 5. On adults, for diseases that normally onset later in life This raises clear ethical problems, as we shall discuss later, but, taking Cystic fibrosis as an example, it also raises other problems. Cystic fibrosis is caused by a single mutant recessive allele on chromosome 7. Heterozygous carriers have normal phenotypes because the recessive CF-allele is masked by the dominant normal allele. However, carriers can pass on the CF-allele to their children. Carriers having fertility treatment will be offered PGD to identify embryos that do not contain two affected alleles. However, doctors will normally test the genes of the developing fetus again during the early part of the pregnancy to guard against false negatives and the possibility that the PGD was wrong.
What is a False negative?
The CF gene mutates in more than 800 different ways. If the person being tested has an unusual mutation their test result may show a false negative. In other words, the test may indicate that the gene is normal when it is, in fact, mutated. Table 1 summarises the frequency of the CF mutation and false negative tests in different ethnic groups in Britain.
1. Preimplantation Genetic Diagnosis
Fig.1 shows the process of Preimplantation Genetic Diagnosis (PGD), which can be used to prevent the birth of babies carrying serious genetic diseases such as cystic fibrosis or sickle cell anaemia.
Ethnic origin European Asian Black Frequency of a CF mutation 1 in 2000 1 in 14000 1 in 90000 Percentage of tests giving false negative 20 65 59
Fig 1. PGD
Egg 1 + Sperm
Typical Exam Question
In the US, every prospective parent is offered the CF test. In Britain, only those at higher than normal risk are tested.
Test genes or chromosomes
5 Test results 6
Genetic disorder excluded
Genetic disorder detected
Incidence in some ethnic groups is very low; Therefore not cost-effective; Some ethnic groups have high false negative rate; There is a risk of prejudice/discrimination against carriers; Freedom of choice/some people do not wish to know
3 Remove one or two cells for testing
2 8 cell embryo
Using the data in Table 1 and your own knowledge, suggest why it may not be sensible to test all future parents in Britain for CF mutations (2)
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2. Pre-natal testing (during pregnancy)
Table 2 summarises the techniques that can be used for pre-natal diagnosis.
Typical Exam Question
Sufferers of Down’s syndrome have an extra copy of chromosome 21 i.e. 3 copies instead of 2 as a result of the chromosomes not separating properly (non-disjunction). Scientists investigated the way in which 323 people with Down’s syndrome were initially diagnosed. All had been screened before 24 weeks of pregnancy by one of three different tests, A, B or C in approximately equal numbers. The results are shown in Table 4.
Technique Amniocentesis What it involves Abnormality detected Removal of small Down’s Syndrome volume of amniotic fluid Spina bifida that bathes the fetus and contains cells from the fetus. The proteins in the fluid can be analyzed as they may be abnormal in spina bifida or the number of chromosomes can be counted (Down’s syndrome sufferers have 3 copies of chromosome number 21) Removal of cells from edge of placenta, most of which is fetal tissue. Provides more DNA than amniocentesis Cystic fibrosis Huntington’s disease Muscular dystrophy
Screening test A No. of cases of Down’s syndrome detected before 24 weeks of pregnancy No. of cases of Down’s syndrome detected at or after birth Total No. of cases of Down’s syndrome 45 B 67 C 41
Chorionic villi sampling
Maternal serum Tests mother’s blood for presence of fetal screening proteins
(a) Which screening test was most successful in detecting Down’s syndrome? (1) (b) Calculate the percentage of cases of Down’s syndrome that were detected before 24 weeks of pregnancy (2) (c) Suggest how the use of these tests could be made more effective (1)
(a) test B (b) 153/281; =54.5% ; (c) combine the tests/ use more than one test;
Ultrasonography Techniques for gaining Organ abnormalities an image of the fetus and fetoscopy
3. New-born babies
About 650,000 babies are born in England and Wales each year. They are all screened for four genetic diseases (Table 3).
Genetic disease Phenylketonuria Incidence Benefits of Test first in UK early diagnosis introduced in 1 in 12000 Diet low in the amino acid phenylalanine prevents severe mental handicap 1 in 4000 Medication prevents severe mental handicap 1969
4. Genetic testing of children
Why test children for genetic disease? The simplest case is when a genetic test is done to confirm a medical diagnosis. For example, if a three year old has blocked lungs, poor digestion and low weight, it makes sense to test them for cystic fibrosis. In families where the dominant disorder familial adenomatous polyposis coli (FAP) is present, there is an increased risk of bowel cancer. If tumors are detected early, they can be removed so children in families where FAP is present are often screened for signs of cancer from the age of 10. Other tests on children are more controversial. For example, the genetic disorder Huntington’s disease (HD) only appears in individuals aged 40+. There are arguments for and against testing a child for the mutation that causes HD.
Sickle cell disease 1 in 4000
Early treatment 2006 reduces symptoms and improves health Early treatment 2007 reduces some symptoms
It allows the parents to prepare for the later care of the individual (they may not be alive to do this themselves of course)
1 in 2500
• • • The child loses the ability to make a future decision about whether to get tested Unlike with adults’ tests, there is a loss of confidentiality If positive, the child may be disadvantaged if people have lower expectations of the child
As you may have realised, tests for CF may be carried out preimplantation, pre-natally and after birth!
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5. Genetic testing of adults
Huntington’s Disease (HD) is late-onset (doesn’t develop until 40 years of age), non-treatable and fatal. So what should a 20-year-old man who knows that HD is in the family do? Is it better not to know and live in hope or take the test and, then, if it’s positive, live the next 20 years knowing that death approaches? How would knowing this affect his decision about a job, a partner, having children?
Typical Exam Question Outline the steps in testing for Huntington’s disease
• • • • • • • • • • identify the gene responsible for the disease Design suitable gene probe for the disease e.g. one complementary to gene / radioactively labelled /fluorescently labelled); extract DNA from patient e.g. by cheek cell swab cut DNA using restriction endonuclease enzyme separate DNA using gel electrophoresis e.g. apply current across agarose/polyacrylate gel DNA moves towards anode smallest fragments move fastest / furthest treat with alkali to make DNA single stranded Use Southern blotting / transfer onto a nylon/nitrocellulose membrane disclosure using x-ray film / UV light / laser
Advantages of taking the test
• • • • • • • • • • • • • • • • peace of mind with negative result knowledge that his children will not have HD if positive, he can choose not to have children or Preimplantation Genetic Diagnosis can be used if positive, he can change his diet to delay onset
Disadvantages of taking the test
no known cure available so increased stress if positive worry that his children may inherit the disease may result in his partner having abortions discrimination by insurers/employers
What makes an effective genetic test?
inexpensive reliable (no false positives) simple and painless rapid turnaround of results counselling follow-up education about the test well advertised complete confidentiality
The success of the Human Genome Project – which has mapped out the entire human genome – is going to identify many more harmful genes which could then be screened for. Some scientists argue that we should screen the entire UK population to find out if they have a genetic predisposition to certain diseases, such as heart disease or lung cancer. Someone who is told that they have a predisposition towards heart disease may than have more regular check-ups and decide to avoid eating excess fats and would not begin smoking cigarettes, for example. The benefits of screening everyone would bring benefits to society as a whole: • It would be easier to determine medical research priorities • Better use could be made of health service budgets by targeting those most at risk • At-risk individuals could be given early treatment, reducing their suffering and reducing later costs • At-risk individuals could be offered genetic counseling about issues such as having children • Many people would receive reduced insurance premiums when it was shown that they were not at risk of genetic disease Other scientists are more cautious, arguing that it could cause serious problems in society: • There is evidence that when people are tested for multifactorial genetic diseases such as diabetes and heart disease, even if they test negative, they become convinced that they are going to get the disease anyway and find it hard to adopt a positive lifestyle – in other words, they become fatalistic • The tests are not predictive – they simply indicate risk – and this is a difficult concept to explain to the public • Increased stress of known sufferers • People who are not at risk may feel that their taxes are not being spent on them • Risk of abuse of the information by vested interests e.g. insurance companies, employers, immigration officers
General advantages and disadvantages of genetic testing/screening
• • • • • • • • • If negative, reduces uncertainty and fear and may increase life-expectancy allows sorting of IVF embryos or PGD individuals can identify if they are carriers of a harmful gene before they have children allows informed decision about IVF /egg/embryo donation so fewer children with genetic disease will be born lower long-term health costs frequency of harmful alleles reduced allows early diagnosis of disease allows earlier treatment of the disease allows parents to prepare emotionally/financially for affected children some test procedures involve risk presence of abnormality may not affect health positive result causes stress and may lead to emotional problems of both affected individual and family members risk of false negative/false positive may lead to an increase in abortions against religious beliefs costly to administer can be used by insurers/employers to discriminate against people
• • • • • • • •
215 Genetic Testing and Screening
Practice Questions 1. Outline the advantages and disadvantages of genetic screening (6) 2. Many IVF couples who carry genes for genetic disorders use PGD to try to ensure that they do not have a child with the disease. The Human Genome Project has now made it possible to test for genes that increase the probability of developing a few types of cancer in later life. The presence of these genes does not mean a person is certain to develop cancer in later life but some genes have been shown to lead to probabilities of developing cancer ranging from 30% to 95%. Outline three ethical problems of using PGD to identify and discard embryos carrying genes for these cancers (3) 3. Since 2007, all babies born in England have been tested for Cystic Fibrosis (CF). This has proved controversial. The table summarises the criteria that are used to decide which genetic diseases should be screened for along with corresponding information about CF. Criteria used to decide which genetic disease should be screened for What is the incidence of the disease? What are the health benefits of screening? Does early detection significantly improve the quality or length of life? CF information
1. Advantages fewer children born with abnormalities / named genetic disorders; pre-natal testing allows parents to prepare for special needs of the child when it is born / early diagnosis may lead to more effective treatment; advanced notice allows more informed life choices; may help parents decide on an abortion; possibly a positive step in evolution of human species as harmful alleles become less common; Disadvantages may increase rates of abortion; false positives / false negatives some tests give probability of disease rather than certainty advanced notice may create stress; may be abused by employers/insurance companies etc; disputes; ethical issues associated with gender/“ideal” phenotype/ eugenics; 2. ethics of discarding potential humans who may never develop cancer; acceptable if risk of death in early life is 100%?; only tets for a small number of types of cancer; new cancer treatments may come before the person develops cancer; could lead to other tests for more minor problems/designer babies. 3. Yes CF relatively common; chance of long term health benefit; maybe cost-effective; prevents anxiety for parents as symptoms develop; enables child to benefit rapidly from any new treatments; identifies the gene in the family and this may inform future decisions about having more children; No cost-effectiveness not proven; anxiety caused by false positives; too many false negatives; need for further testing; health benefits not proven;
1 in 2500
Results are varied. Some studies show long term health benefits but others don’t. It is too early to know whether detection increases longevity Screening = £6400 for every case identified. Early diagnosis may reduce the overall cost of care by more than this 10% of tests give false negatives –the faulty gene is not detected. 7% of tests give false positives
How much does screening cost relative to the cost of treating and caring for a patient with the disease?
How reliable is the test?
Was the introduction of CF screening for every baby a sensible policy? (6)
Acknowledgements: This Factsheet was researched and written by Kevin Byrne. Curriculum Press, Bank House, 105 King Street, Wellington, Shropshire, TF1 1NU. Bio Factsheets may be copied free of charge by teaching staff or students, provided that their school is a registered subscriber. No part of these Factsheets may be reproduced, stored in a retrieval system, or transmitted, in any other form or by any other means, without the prior permission of the publisher. ISSN 1351-5136