Alpha thalassaemia due to non-deletional mutations on the -3.7 alpha globin fusion gene: laboratory diagnosis and clinical importance

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Alpha (α) thalassaemia may be caused by large deletions of the α globin gene(s), or rarely, non-deletional mutations. Both types of mutations may co-exist, and if located on the same allele (α), produce a reproductive risk of hydrops fetalis. We illustrate how clinical-laboratory correlation and accurate α gene sequencing are essential in identifying such patients. Nine asymptomatic patients with -α thalassaemia trait were noted to have significant microcytosis that was insufficiently explained by a single α deletion. Hence α1 and α2 globin gene sequencing were performed, which detected a non-deletional mutation in all patients. A new set of α1 specific primers were designed for separate sequencing of the α1 gene and the -α fusion gene, respectively, so that the non-deletional mutation could be localised to the correct allele. In six of nine patients tested, the non-deletional mutation was on the α1 globin gene. In three patients the mutation was located on the -α fusion gene. The latter group functionally has an α allele (αα/-) with a reproductive risk for Hb Barts hydrops fetalis. Non-deletional mutations can occur on the α globin gene or a fusion gene such as the -α allele. Identification and accurate localisation of these mutations is important as this can have significant reproductive implications.