The molecular basis for the thalassaemias in Sri Lanka

Abstract

Summary. The b-globin gene mutations and the a-globin genes of 620 patients with the phenotype of severe to moderate thalassaemia from seven centres in Sri Lanka were analysed. Twenty-four b-globin gene mutations were identified, three accounting for 84AE5% of the 1240 alleles studied: IVSI-5 (G fi C) 56AE2%; IVSI-1 (G fi A) 15AE2%; and haemoglobin E (codon (CD)26 GAG fi GAA) 13AE1%. Three new mutations were found; a 13-bp deletion removing the last nucleotide in CD6 to CD10 inclusively, IVSI-129 (A fi C) in the consensus splice site, and a frame shift, CD55 (-A). The allele frequency of a + thalassaemia was 6AE5% and 1AE1% for -a 3AE7 and -a 4AE2 deletions respectively. Non-deletion a-thalassaemia was not observed. Triplicate or quadruplicate a-globin genes were unusually common. In 1AE5% of cases it was impossible to identify b-thalassaemia alleles, but in Kurunegala detailed family studies led to an explanation for the severe thalassaemia phenotype in every case, including a previously unreported instance of homozygosity for a quadruplicated a-globin gene together with b-thalassaemia trait. These findings have implications for the control of thalassaemia in high-frequency populations with complex ethnic histories.

The Role of the Inherited Disorders of Hemoglobin, the First “Molecular Diseases,” in the Future of Human Genetics

“…Although mild β thalassemia mutations occur sporadically in some parts of Asia, and when inherited together with HbE give rise to a relatively mild phenotype, they are exceptionally rare in Sri Lanka; of over 40 β thalassemia mutations identified, only one is of the mild variety, and it has been found in only one patient (31). Thus the heterogeneity of the phenotype cannot be explained by the effect of a primary modifier.…”

“…First, there is the coinheritance of the mild form of α + thalassemia due to the loss of a single α gene, which occurs at a very high frequency right across the tropical belt (109). In Sri Lanka about 14% of the population carry this mutation (31), and if it is coinherited with HbE β thalassemia, it always produces a dramatic phenotypic change characterized by an extremely mild non-transfusion-dependent disease (70,85). The coinheritance of α thalassemia has also been found to cause a modest amelioration of the phenotype of some forms of β thalassemia and even sickle cell anemia, but the effect is nowhere near as dramatic as in HbE β thalassemia (109).…”

A Journey in Science: Early Lessons from the Hemoglobin Field

“…The primary modifiers are the β thalassemia mutations of varying severity. Modifiers of this type turned out to be irrelevant in Sri Lanka because, of over 40 different β thalassemia mutations that have been identified, all but one are of the extremely severe variety (44). The secondary modifiers are those that involve the other globin gene loci.…”

Understanding Beta-Thalassemia with Focus on the Indian Subcontinent and the Middle East

“…Different classes of HBB mutations underlie betathalassemia, in descending order of frequency: missense/nonsense [25,26], splicing [27], regulatory [28], small or gross gene deletions [27,29], including the common deletion of the terminal portion of HBB [30], gene insertions [31], small insertion-deletions [32], and complex rearrangements [33]. In rare instances, the causative defect is due to a deletion of the LCR [18], mutations in another gene within [34] or outside [16] the beta-globin locus.…”