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.

During a study of the molecular basis for severe forms of ␤ thalassemia in Sri Lanka, 2 patients were found to be heterozygous for ␤ thalassemia mutations. Further analysis revealed that one of them has a previously unreported molecular basis for severe thalassemia intermedia, homozygosity for quadruplicated ␣ globin genes in combination with heterozygous ␤ thalassemia. The other is homozygous for a triplicated ␣ globin gene arrangement and heterozygous for ␤

The thalassemias pose an increasing burden for health-care services in many Asian countries. In order to conserve rare resources, it is essential to determine the reasons for the remarkable phenotypic heterogeneity and natural history of these disorders so that the most cost-effective methods for their control and management can be established. A long-term observational study of patients with different forms of thalassemia in Sri Lanka suggests that in addition to the well-defined primary, secondary and tertiary genetic modifiers, environmental factors, particularly malaria, and variation in the ability to adapt to the profound anaemia which characterizes these conditions, may play a significant role in determining their clinical severity. These findings may have important implications for the control and management of thalassemia in Asian populations.