Oman is one of the countries of the Arabian Peninsula that, in a few decades, has changed from a traditional nomadic culture to a modern industrialized society. In this rapid process, public health has made dramatic progresses fighting against diseases endemic in the country and is now facing the problem of severe hereditary recessive conditions like sickle cell disease (SCD) and beta thalassemia major (BTM). Carriers of this disease are frequent in the country because they were protected against Malaria during millennia of evolution and being in Oman consanguinity a socio-cultural habit, the incidence of children born with hemoglobinopathy is high in many areas of the country. As shown by experiences made in other countries, management of these severe diseases consists of identifying the mutation spectrum, drawing a genotype-phenotype correlation, selecting the best possible supportive treatment and implementing primary prevention methods for couples at risk. Oman has an extended network of structured hospitals where local patients receive care and treatment free of charge. Pre-matrimonial counseling clinics are widely distributed in the country; their policy is to identify carrier couples prior marriage, offering as the only option to alter the partner choice whenever a presumed genetic risk has been suspected at the protein level. However, healthy carriers of SCD and BTM may have progeny with striking variability in phenotype and response to therapy may depend on the inheritance of more or less severe mutation and other complex genetic factors. The precise genetic changes prevalent in the different regions of Oman and analysis of the genotype/phenotype relationship of the disease still remain inadequately studied in the country. The aim of this thesis is to study in detail the molecular spectrum of globin gene mutations and other modifying factors among the different regions in the country by studying a large number of samples to cover the entire population to a) reflect the geographical and historical backgrounds of each region from the described mutations; b) document the mutation spectrum of β- and α- thalassemia to facilitate national screening and educational programmes; c) facilitates genetic pre-matrimonial counseling and testing for the purpose of better risk prediction; d) allow a more tailored treatment for the affected children based on a well characterized genotype and e) the possibility to offer prevention by prenatal diagnosis and the option of medical interruption of pregnancy when necessary, with approval by public health and religious authorities, as is the case in other modern Muslim countries. Chapter 1 (General introduction) includes general knowledge on the hemoglobinopathies, the relevant genes, modifying factors, world prevalence and treatment options. Chapter 2 focuses on the country of Oman and gives a general view on the problem of hemoglobinopathies in Oman. Chapter 3 describes prevention options and the bottlenecks. Chapter 4 describes the general molecular spectrum of β-thalassemia and α-thalassemia in Oman. A broader spectrum of regional epidemiology and distribution of β-thalassemia and β-variants mutations among the different Omani subdivisions is outlined in Chapter 5. Chapter 6 presents two cases that were characterized during our studies; the first describing a novel Omani mild beta-thalassemia mutation; the second presenting an alpha gene variant in an Omani family that was assumed to lead to a lethal condition in the offspring. The spectrum of alpha-thalassemia in Oman including large deletions and point mutations is described in Chapter 7. The molecular spectrum of deltathalassemia in Omani cases associated with low HbA2 levels is illustrated in Chapter 8. Chapter 9 describes the map of the haplotype distribution of homozygous HbS/S sickle cell disease as well as sub-haplotypes in otherwise identical beta clusters to support genotype/phenotype correlation. Chapter 10 studies the effect of Hydroxyurea treatment in Omani sickle cell disease in association with XmnI polymorphism. Alpha thalassemia whether a risk or a modulation factor in homozygous Omani HbS/S is underlined in Chapter 11. Chapter 12 describes the design of uniand bi-directional barcoded new generation molecular methodology using Ion Torrent PGM to detect β-mutations in a cohort of Omanies with β-hemoglobinopathy to keep up with the new technologies and scientific advances. Chapter 13 focuses on the views of Omani carrier-couples towards prevention options in view of the ethnic, social and cultural background. Chapter 14 includes the final discussion and conclusion on hemoglobinopathies in Oman and presenting also the limitations encountered when offering modern prevention.

Oman is one of the countries of the Arabian Peninsula that, in a few decades, has changed from a traditional nomadic culture to a modern industrialized society. In this rapid process, public health has made dramatic progresses fighting against diseases endemic in the country and is now facing the...