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Title: The molecular basis of thalassaemia in Sri Lanka
Author: Fisher, Christopher A.
ISNI:       0000 0001 3466 0814
Awarding Body: Oxford Brookes University
Current Institution: Oxford Brookes University
Date of Award: 2002
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Blood samples from over 1600 schoolchildren revealed a prevalence of both trait and HbE trait, averaging 2.3% and 0.8% respectively. With the present popUlation estimate at 18.6 million, it is predicted that approximately 2650 patients with l3-thalassaemia major and 956 with HbE/I3-thalassaemia should consume >5% of the current health budget for treatment of these patients. Patients with the phenotype of severe thalassaemia, from seven centres, were analysed to understand the molecular basis of the disease. Twenty-four l3-globin gene mutations were identified with three mutations accounting for 84.4% of the 1234 alleles: IVSI-5 (G--7C) 56.1 %; IVSI-l (G--7A) 15.2% and HbE 13.1 %. Sixteen mutations have previously been described on the Indian subcontinent and demonstrate close regional links between the popUlations, especially North East India, and were supported by haplotype association. The IVSI-l (G--7A) mutation occurs commonly in countries around the Mediterranean but very rarely on the Indian subcontinent. In Sri Lanka it is associated with a different 3' haplotype, suggesting a multicentric origin. Three new mutations were found; a frameshift codon 6-10 IVSI-129 (A--7C) in the consensus splice site and a second frame shift, CD55 (-A). Four a-gene arrangements were demonstrated. An allele frequency of the a+-thalassaemia gene deletions were 6.5% and 1.1% for the _a3.7 deletion and the _a4.2 deletion, respectively. Cord blood analysis of Hb Bart's levels confirmed an estimated level of 7.1 % for a single a-gene nonexpression. Extra a-genes are common and the first instance of homozygosity for the aaaa arrangement was observed. No aOthalassaemia was revealed and only a single polymorphism was associated with a possible extremely mild a-thalassaemia allele. The phenotype associated with the various l3-globin genotypes was found to be extremely variable. Within the many factors that modify this phenotype the Xmn-I polymorphism was significantly associated with the level of haemoglobin expressed. A +1+ genotype appeared to be a good indicator of a milder outcome. The incidence of a-gene deletions was low in patients with HhElI3-thalassaemia and thus proposed this as a strong modifier for a mild phenotype. Other factors were associated with specific complications.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral