Thalassaemia Risk in One Family: Recurrence, Twins and a Sibling's Children
A couple from a district where the β-thalassaemia carrier frequency is about 1 in 30 have a 6-year-old child diagnosed at 8 months with transfusion-dependent β-thalassaemia major. Both parents are clinically healthy, with normal haemoglobin but MCV of 78 fL, which is borderline low. The mother is pregnant again, and an ultrasound at 10 weeks shows dichorionic diamniotic twins. The haematologist has ordered prenatal DNA testing, but the anxious family asks three questions: will 'the same thing' happen again, does the fact that the first child is affected mean the twins will somehow 'balance out', and what is the risk for the children of their unaffected 12-year-old son? The 12-year-old's future wife would come from the same district with no family history of thalassaemia, and the geneticist is willing to use the population carrier frequency for her.
1. Deduce the mode of inheritance and the parents' genotypes, and state the recurrence risk with reasoning.
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Two unaffected parents with an affected child indicates a recessive condition; the fact that the affected child is homozygous for a severe globin defect while both parents are haematologically normal (only microcytosis, no anaemia) fits autosomal recessive β-thalassaemia, not an X-linked or dominant pattern. Each parent must be a carrier of one β-thalassaemia allele (genotype β/β⁰ or β/β⁺), and the affected child is homozygous (β⁰/β⁰ or equivalent), having inherited one variant allele from each parent. Each parent is an obligate carrier because an affected child can only be produced if both gametes carried a variant.
At each conception the possible offspring are 1/4 homozygous affected, 1/2 carriers (clinically healthy, like the parents) and 1/4 homozygous normal.
Judgement: the recurrence risk is 1 in 4 for every pregnancy, and it is not reduced by the fact that one child is already affected. Prenatal DNA testing is appropriate for the current pregnancy, and parental testing should confirm that each carries a distinct variant so that the laboratory knows what to look for in the twins.
2. The twins are dichorionic. What are the chances for them, and is the 'balancing out' idea valid?
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Dichorionic diamniotic twins are usually dizygotic, so treat them in the first instance as two independent conceptions, each with the same 1/4 affected, 3/4 unaffected probability.
Both unaffected = (3/4)² = 9/16 ≈ 56.3%. Both affected = (1/4)² = 1/16 ≈ 6.3%. Exactly one affected = 2 × (1/4)(3/4) = 6/16 = 37.5%. These sum to 1, as they must.
No 'balancing' is possible: each conception is an independent event, and an affected first child carries no information that shifts the next child's probability. The only mechanism that would make the twins concordant is monozygosity, and about 10–15% of dichorionic pairs are monozygotic; if the twins are monozygotic they share a genotype, so both would be affected or both unaffected, with probabilities 1/4 and 3/4 rather than 1/16 and 9/16.
Judgement: quote 9/16 for both unaffected only with the dizygotic assumption stated, and note that DNA testing of both twins resolves the monozygotic question and the counselling uncertainty. The parents should not be reassured by the first child's illness, nor frightened by a 6.3% chance of both twins being affected.
3. Estimate the risk that the unaffected 12-year-old son will have an affected child, and say what would change the figure.
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First establish the son's carrier probability. He is unaffected, so he is either homozygous normal (1/4 of all offspring, i.e. 1 of the 3 unaffected parts) or a carrier (2 of the 3 unaffected parts). Given that he is unaffected, P(carrier) = 2/3.
Assume his future wife is an unrelated woman from the district with no family history, so P(carrier) = 1/30. If both are carriers, each child has a 1/4 chance of being affected.
P(affected child) = (2/3) × (1/30) × (1/4) = 2/360 = 1/180 ≈ 0.56%.
Judgement: this is reassuring - about 1 in 180, not the 1 in 4 that applies to the parents. The figure is dominated by the assumed 1/30 carrier rate and by the 2/3, and it is conditional on her being an unrelated woman from that district; if she were a relative, or came from a higher-prevalence region, the risk would rise. If she is screened and found not to carry any of the common β-thalassaemia variants, the risk falls to a small residual value from rare variants, which is why carrier screening of the partner is the single most useful action.