Qubbaj, Wafa Ahmed; (2003) Approaches towards the prevention of haemoglobinopathies in Jordan. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The basic aim of this thesis was to define a suitable approach for the prevention of thalassaemia in Jordan. A detailed epidemiological analysis produced an estimate of 103 annual affected births and 415 annual at-risk pregnancies. Premarital screening has been introduced in Jordan: estimates show approximately 144 new at-risk couples annually. Molecular analysis of 172 thalassaemia major and 107 thalassaemia intermedia patients permitted the full spectrum of thalassaemia mutations in Jordan to be defined. 25 different mutations were identified. A high frequency of the "pure" homozygous genotype was found in both thalassaemia major (63.5%) and thalassaemia intermedia (67.3%) patients, associated with the local preference of consanguineous marriage. A detailed description of the genotypes and corresponding clinical picture of the thalassaemia intermedia patients was achieved. An unusually high prevalence of the mild -thalassaemia mutation IVS 1-6 was found (53% of the total), and 45% of thalassaemia intermedia patients had this mild genotype. Screening for carriers is by measurement of the red cell indices and quantitation of haemoglobin A2 level. Analysis of the indices of 137 obligate beta thalassaemia heterozygotes showed that for screening the appropriate cut-off of mean cell haemoglobin (MCH) is 25.7pg. When equivocal or borderline results in MCH or Hb A2 level are found, then the IVS 1-6 or -87 mutations should be sought by DNA methods. As IVS 1-6 was the commonest mutation in the samples studied and the commonest homozygous genotype in the thalassaemia intermedia patients, an in depth clinical study was carried out in the 48 patients with homozygous IVS 1-6 to gain more information on the appropriateness of offering a prevention service for this mild genotype. Clinical severity ranged from very mild to severe. Notably there was an association of haplotype VI with the mild phenotype, demonstrating the influence of variations in non-coding DNA (haplotype) on the expression of the IVS 1-6 mutation. The psychosocial burden associated with mild thalassaemia intermedia was studied in 59 thalassaemia intermedia patients and 51 parents. It was found, despite the generally mild clinical picture, that there was a high psychosocial burden for patients and parents. This led to a higher level of interest in prenatal diagnosis than had been anticipated. The research shows the importance of DNA genotyping prior to genetic counselling of at-risk couples, and highlights the importance of specialist genetic counselling particularly for the mild beta thalassaemia mutations. It also shows the relevance of DNA genotyping for appropriate clinical management of the affected patients. Prenatal diagnosis was demonstrated to be feasible and acceptable to at-risk couples in Jordan. There was a high level of interest in preimplantation genetic diagnosis in some families. Suitable PCR methods using direct detection of mutations, linkage and STR analysis for the reliable detection of the common mutations, found in the Jordanian population, were demonstrated. This thesis provides evidence on which policy decisions for the prevention of thalassaemia in Jordan can be based.

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