Question

1. Alpha thalassaemia is a blood condition resulting from abnormal haemoglobin production, due to loss of function of copies of either HBA1 or HBA2 genes. These genes are very similar and next to each other on the chromosome; for simplicity’s sake we talk about having four copies of the HBA gene (two alleles, with two HBA copies on each allele).

Alleles are depicted with α representing a functioning HBA gene, and - representing a non-functioning gene. For example, the genotype α-/αα represents someone with one allele with only one HBA copy functioning, and a second allele with both HBA copies functioning.

There are multiple phenotypes of alpha thalassaemia, which generally depend on how many of the four HBA copies are functioning. This is outlined in the table below:

Phenotype	Genotype	Symptoms / severity
α-thalassaemia major	Loss of 4 HBA genes	Severe onset from birth - death usually occurs in newborn period
Haemoglobin H (HbH) disease	Loss of 3 HBA genes	Generally severe - anaemia, possible bone issues, may require blood transfusions
α-thalassaemia trait	Loss of 2 HBA genes	Generally mild - usually only detectable via blood cell investigation
α-thalassaemia silent carrier	Loss of 1 HBA gene	No or few symptoms - often not detectable even via blood cell investigation

Both Indian and Southeast Asian populations have relatively high rates of alpha thalassaemia.

In Indian populations, alleles with one HBA gene copy deleted are the common cause of alpha thalassaemia conditions. Alleles with both HBA gene copies deleted are rare.

In Southeast Asian populations, alleles with both HBA gene copies deleted are the common cause of alpha thalassaemia conditions. Alleles with one HBA gene copy deleted are rare.

You are providing genetic counselling to an Indian couple, both of whom have alpha thalassaemia trait due to mutations commonly seen in their population.

Regarding alpha thalassaemia, what are the phenotypes possible for a pregnancy for this couple? Give the chance of each phenotype.

Answer 1

Advances in chelation treatment along with regular transfusions have introduced a new era for the thalassemic population, increasing the average life span and rendering the perspective of reproductive capacity attainment and creation of a family, a rational goal for patients and a great task for relevant clinicians. Pregnancy in TM and TI should be considered a high-risk pregnancy, although gestation can be completed safely for both mother and fetus as long as pregnant women follow close screening and are referred to thalassemia specialists. However, as different experts suggest, a standard management plan should be applied to this group of pregnant women,138 starting with a complete preconception assessment, in order to evaluate and reduce possible risks during pregnancy. Evaluation should include thorough checking for hormonal abnormalities, infectious diseases, liver function, and coagulation status. Women carefully managed and well chelated during preconception usually carry out a successful gestation and labor. Hemoglobin concentration must be maintained over 10 g/dL, and chelation must be stopped as soon as pregnancy is diagnosed. The most important factors to be assessed are cardiac function and iron load, using accurate MRI techniques. In cases of left ventricle-dysfunction development during gestation, and bearing in mind the maternal benefits and the potential fetal risks, DFO could be considered, especially after the critical period of organogenesis. Although CS subtracts from the additional stress of labor, it is usually limited to similar cases as in the general population, and time and mode of delivery should be individualized.