Alpha thalassemia is one of the most widespread genetic diseases worldwide, with frequencies of the carrier state reaching up to 80 – 90% in some areas . The incidence is approximately 25 – 30% in tropical Africa , while in the Arabian Peninsula, the frequency varies from a low of close to zero in the desert areas to as high as 60% in the agricultural zones of Eastern Saudi Arabia [3, 4].
The normal individual has a complement of four α-globin genes (αα/αα), any one of which can be absent, producing varying degrees of alpha thalassemia . In α0 alleles, both genes on a chromosome are deleted (--), while in α+, a variable portion of the α2 and/or α1 gene is deleted, resulting in a reduction in chain synthesis. The size of the deletion in α0 alleles is variable, and each is named for the part of the world where it is prevalent. Thus --MED, --FIL, and --SEA deletions are found in the Mediterranean, Philippines and South East Asia, respectively . The α+ deletions are designated by their sizes, and the most common is the –α-3.7 kb allele. One- or 2-gene deletions (-α/αα, -α/-α, --/αα) produce the a-thal trait, which is usually associated with mild microcytic and hypochromic anemia. The loss of 3 genes (--/-α) produces classical hemoglobin H (HbH, β4 tetramer) disease, which is characterized by moderate to severe anemia. The loss of all 4 genes (--/--) causes Hb Barts (γ4) hydrops fetalis, which is incompatible with life in the absence of the early onset of chronic transfusion or stem cell transplantation .
Apart from deletions, there are a few point mutations that affect the transcriptional efficiency of the α-globin genes and are designated αTα or ααT depending on whether the α2 or α1 gene is affected . These nondeletional α-thalassemia alleles commonly affect the promoter, initiation codon (ATG), splicing signals (GT/AG), termination codon (TAA), and polyadenylation signal (AATAAA) of the affected gene. The most common of these are αIVSI(-5nt)α (in the Mediterranean deletion), polyadenylation site mutations α2AATAAG, α2AATGAA and α2AATA-- (in the Mediterranean and Middle East deletions) [7-11], and termination codon mutations leading to elongated Hb variants, such as Hb Constant Spring (HbCS), Hb Icaria, Hb Koya Dora, Hb Seal Rock and Hb Pakse [12-14]. Heterozygotes for these alleles have a thalassemia minor phenotype, but homozygotes and compound heterozygotes often have HbH disease of varying severity and blood transfusion requirements.
The a-thalassemia frequency is approximately 30 – 40% in Kuwait, and HbH disease is mostly linked to the polyadenylation (polyA, αPA-1) mutation [15, 16]. However, there has been no comprehensive study of the spectrum of alpha thalassemia alleles in the country. The present study was carried out to document the frequencies of moderate to severe alpha thalassemia phenotypes among patients referred for molecular diagnosis. In particular, it aimed to investigate the presence of the α0 allele in the population and to determine the possibility of having a newborn with alpha thalassemia major (Hb Bart’s hydrops fetalis) [1, 17]. This will enable more purposeful counseling of patients and empower physicians in the identification of patients who require further investigations. To this end, we analyzed all cases of suspected α-thalassemia referred to the hemoglobin research laboratory at Kuwait University over a 20-year period.