Haemoglobinopathies are among the most common inherited monogenic disorders worldwide. Thalassaemia screening for carrier status is recommended for adults of reproductive age if suspected of being at risk. Conventional laboratory methods for screening include the assessment of haematological indices, and high-performance liquid chromatography, capillary electrophoresis or isoelectric focusing to measure the levels of HbA 2 and HbF, and to identify haemoglobin variants. Each screening method has its advantages and disadvantages, the main disadvantage being that none can fully resolve all variants. The complex nature of the genetics of haemoglobinopathies necessitates expertise in the interpretation of screening results to evaluate the most likely genotypes, which must then be confirmed using the DNA diagnosis. This review highlights the limits and pitfalls of each screening technique, and outlines a rational combination of different methods to overcome issues in thalassaemia carrier detection.
Highlights
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Measurement of RBC indices and HbA 2 and HbF percentages are essential for thalassaemia screening.
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Co-inheritance of globin gene variants with β-thalassaemia mutations can alter levels of HbA 2 .
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Methods currently used to measure total haemoglobin are unable to distinguish all variants fully.
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Selection of the best approach for a laboratory will be guided by prevalence of variants in the region.
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Only DNA testing methods can distinguish the true nature of the thalassaemia.
Introduction
Anaemia is a major public health problem, affecting the lives of more than two billion people worldwide, representing approximately 30% of the global population . Women are particularly susceptible, with over 38% of pregnant and almost 30% of non-pregnant women being affected . Iron deficiency is the cause of anaemia in around 50% of cases , but iron-deficient anaemia (IDA) is clinically indistinguishable from thalassaemia. It is important to differentiate these conditions to determine the underlying cause of IDA (for example, menstrual complications or cancer) and to avoid unnecessary iron therapy for thalassaemia, with its related haemosiderosis, leading to serious complications, including cardiomyopathy, hepatic fibrosis and endocrine dysfunction .
Thalassaemia is inherited as an autosomal recessive disorder; therefore, a child of two carrier parents has a 25% chance of being unaffected, a 25% chance of being affected, and a 50% risk of also being a carrier. Haemoglobinopathies contribute nearly 3.4% to overall worldwide mortality of children aged under five years . Clinical presentation for thalassaemia carriers ranges from almost asymptomatic to severe anaemia requiring lifelong blood transfusions . Because of this health burden, many countries with high prevalence of thalassaemia are committed to the implementation of control measures, including carrier screening and prenatal diagnosis. Couples with a family history of thalassaemia planning to have children are advised to have haemoglobinopathy screening, followed by appropriate genetic counselling. The risk of passing on a major thalassaemia should be thoroughly explained, and the information provided should be aimed at aiding decisions on reproduction. The severity of disease that the child may potentially inherit depends upon the combination of the parent’s genotypes and the number of affected genes co-inherited ( Figure 1 ). Complete DNA testing prior to commencement of any treatment is required to determine prognosis and appropriate therapy.
