A Thalassaemia Family: Working Out the Risk and Weighing the Options
A married couple, both 30 years old, are healthy and not related. Their 5-year-old daughter was diagnosed with beta-thalassaemia major at 8 months of age; she needs a blood transfusion every 4 weeks and her haemoglobin is maintained at about 9 g/dL. Haemoglobin electrophoresis shows the father has HbA 95 %, HbA2 4.8 % and HbF 1.2 %, the mother has a similar pattern, and the daughter has HbF 92 % with no HbA. The wife is now 12 weeks pregnant. In their community about 1 in 20 people carries a beta-thalassaemia allele. The husband says, 'Our second child will be fine because my wife took folic acid this time,' and an uncle advises them to skip testing and 'let nature decide'. The clinic offers chorionic villus sampling at 11–13 weeks, with the option of terminating an affected pregnancy, which the couple's religion does not normally permit.
1. Using a genetic diagram, work out the probability that the unborn baby will have thalassaemia major, and the probability that it will be a healthy non-carrier. Then address the husband's claim about folic acid.
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Genotypes. The parents are healthy but each has an affected child, so both must be carriers: Tt, where T is the normal beta-globin allele and t is the thalassaemia allele. The daughter, with no HbA at all, is tt.
Genetic diagram. Father's gametes: T and t. Mother's gametes: T and t. Crossing them gives four equally likely combinations: TT, Tt, Tt, tt.
Probabilities for each pregnancy.
- tt (thalassaemia major): 1 in 4, i.e. 25 %.
- TT (healthy, non-carrier): 1 in 4, i.e. 25 %.
- Tt (healthy carrier): 2 in 4, i.e. 50 %.
The risk is the same for every pregnancy and is not affected by the previous child being affected.
The folic acid claim. Folic acid reduces the risk of neural tube defects such as spina bifida; it has no effect on which beta-globin alleles an embryo inherits. The genotype is fixed at fertilisation. A supplement cannot change the 1 in 4 probability, so the husband's reasoning is incorrect and he should be told so clearly but kindly.
2. Explain why the couple's healthy children have a 2 in 3 chance of being carriers, and why a harmful recessive allele is still found in about 1 in 20 people.
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Why 2 in 3. Start from the four equally likely outcomes: TT, Tt, Tt, tt. Once you know the child does not have thalassaemia, the tt outcome is excluded and only three outcomes remain - TT, Tt and Tt. Two of those three carry the allele, so the conditional probability is 2/3 (about 67 %). Note this is not the 50 % figure that applies before the child's health is known.
Why the allele is common.
- It is recessive, so carriers are completely healthy and are not removed from the population by selection. Nothing selects against them before they have children.
- Heterozygous carriers have some protection against malaria, so in malarial regions the allele has been favoured historically and kept at a relatively high frequency.
- Marriage within a community or extended family raises the chance that two carriers meet.
Population arithmetic. With 1 in 20 carriers, the chance that two random people are both carriers is 1/20 × 1/20 = 1/400, and the chance of an affected child is a quarter of that, about 1 in 1,600. Because the parents already know they are both carriers, their own risk stays at 1 in 4 for each pregnancy.
3. Evaluate the couple's options, including prenatal diagnosis and gene therapy, and state what the clinic should tell them.
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Prenatal diagnosis. Chorionic villus sampling at 11–13 weeks obtains fetal cells and can identify whether the fetus is TT, Tt or tt. It gives information, not treatment. It carries a small risk of miscarriage (roughly 1 %), and its value depends on what the couple would do with the result. Under their religious view they may decline testing, or test only to prepare for the birth of an affected child, such as arranging early transfusion. Counselling must be non-directive: the decision belongs to them.
Gene therapy. The aim is to insert a working beta-globin gene into the patient's own blood-forming stem cells so that normal HbA is produced. It is not a simple cure: it requires chemotherapy to clear the bone marrow, carries risks of insertional damage and immune reaction, needs long follow-up, and is extremely expensive and not routine care in Malaysia. It should be described as a developing option, not something available tomorrow.
Other options. A matched sibling could donate bone marrow, but conceiving a child partly as a donor raises serious ethical questions. Good transfusion plus iron chelation remains the mainstay.
What the clinic should do. Give the 1 in 4 figure clearly, correct the folic acid misunderstanding, explain each option with its risks and costs, and support whichever choice the couple makes.