The molecular genetics of alpha globin gene ex pression in the native Omani population: towards an understanding of the molecular basis of alpha thalassaemia and impact on clinical ex pression of beta thalassaemia and sickle cell disease

Executive Summary Summary The purpose of the project is to diagnose subjects with Hypochromic microcytic red blood cell with or with out anemia accurately, when both nutritional anemia and or beta thalassaemia trait could not explain it. We aim to characterize the Alpha gene in our Omani population, which will help in the diagnosis of Alpha thalassaemia cases and premarital counseling. Alpha and beta thalassaemia are reported widely in Arab populations at variable frequencies and often in coexistence with the structurally abnormal hemoglobin like HbS or HbC or HbD. Since the spectrum of the most common mutations associated with beta-thalassaemia in the Omani population has been already characterized, here we propose to characterize molecular features of alpha-thalassaemia, in Omani population. Subjects for study will be recruited from three cohorts. The samples [n=500] collected in the National Neonatal Screening Program that has just been concluded under the auspices of the His Majesty's Strategic project grant will form the first cohort. Additionally, a second cohort of adult 250 subjects with sickle cell disease in steady state will be selected from the Hematology Outpatient Clinics on the basis of their CBC tests (Hemoglobin (Hb), mean corpuscular volume (MCV), Red Cell Distribution Width (RDW) and their hemoglobin electrophoresis results. Patients with microcytosis [MCV and lt;74 fl] and hypochromia [MCH and lt;32 pg] will be the target group for further analysis and clinical comparative evaluation. Their nutritional status will also be included in the study [S. Ferritin] We will also study another cohort of 250 normal blood donors after an informed consent with a Complete Blood Count and HPLC to study and evaluate the role of alpha thalassaemia on microcytosis v/s the role of Iron deficiency and/or beta thalassaemia trait. Molecular screening for the suspected thalassaemia cases will involve detection of single or double gene deletion, gene triplication and point mutations (e.g. and alpha;TSaudi) by means of GAP PCR, gene dosage analysis[Genescan] and DNA sequencing. This is the first study that attempts to characterize the molecular basis of and alpha;-thalassaemia in Omani population and can have significant impact on future detailed studies essential for effective patient management, premarital counseling and prenatal and pre-implantation genetic diagnosis. We will also study the interactions of alpha thalassaemia on structural and non-structural defects of hemoglobin like beta thalassaemia and sickle cell disease. It will help characterize the role of alpha thalassaemia gene on the clinical behavior and phenotype of these disorders when they co-exists. The project proposal is being submitted for funding from the Research Council, Oman after approval from the local medical research and ethics committee [MREC].

Executive Summary Summary The purpose of the project is to diagnose subjects with Hypochromic microcytic red blood cell with or with out anemia accurately, when both nutritional anemia and or beta thalassaemia trait could not explain it. We aim to characterize the Alpha gene in our Omani population, which will help in the diagnosis of Alpha thalassaemia cases and premarital counseling. Alpha and beta thalassaemia are reported widely in Arab populations at variable frequencies and often in coexistence with the structurally abnormal hemoglobin like HbS or HbC or HbD. Since the spectrum of the most common mutations associated with beta-thalassaemia in the Omani population has been already characterized, here we propose to characterize molecular features of alpha-thalassaemia, in Omani population. Subjects for study will be recruited from three cohorts. The samples [n=500] collected in the National Neonatal Screening Program that has just been concluded under the auspices of the His Majesty's Strategic project grant will form the first cohort. Additionally, a second cohort of adult 250 subjects with sickle cell disease in steady state will be selected from the Hematology Outpatient Clinics on the basis of their CBC tests (Hemoglobin (Hb), mean corpuscular volume (MCV), Red Cell Distribution Width (RDW) and their hemoglobin electrophoresis results. Patients with microcytosis [MCV and lt;74 fl] and hypochromia [MCH and lt;32 pg] will be the target group for further analysis and clinical comparative evaluation. Their nutritional status will also be included in the study [S. Ferritin] We will also study another cohort of 250 normal blood donors after an informed consent with a Complete Blood Count and HPLC to study and evaluate the role of alpha thalassaemia on microcytosis v/s the role of Iron deficiency and/or beta thalassaemia trait. Molecular screening for the suspected thalassaemia cases will involve detection of single or double gene deletion, gene triplication and point mutations (e.g. and alpha;TSaudi) by means of GAP PCR, gene dosage analysis[Genescan] and DNA sequencing. This is the first study that attempts to characterize the molecular basis of and alpha;-thalassaemia in Omani population and can have significant impact on future detailed studies essential for effective patient management, premarital counseling and prenatal and pre-implantation genetic diagnosis. We will also study the interactions of alpha thalassaemia on structural and non-structural defects of hemoglobin like beta thalassaemia and sickle cell disease. It will help characterize the role of alpha thalassaemia gene on the clinical behavior and phenotype of these disorders when they co-exists. The project proposal is being submitted for funding from the Research Council, Oman after approval from the local medical research and ethics committee [MREC].