The Molecular Pathology of β-Thalassemia in Turkey: The Boğaziçi University Experience

Abstract

The thalassemias are a diverse group of hemoglobin (Hb) disorders characterized by a reduced synthesis of the globin chains of Hb. Today, more than 200 mutations, affecting different levels of β-globin gene expression, by a variety of mechanisms, are known to result in a β-thalassemia (thal) phenotype. According to recent findings, the multilayered complexity in the phenotype of β-thal is the result not only of marked molecular heterogeneity at the β-globin locus, but at the level of several other genes as well. The heterogeneity at the β-globin locus, which is the most reliable and predictive factor of disease phenotype, is simplified, to a certain extent, by the fact that the mutations are ethnic-group specific. Fifty out of >200 β-thal mutations account for 90–95% β-thalassemias worldwide. In the broad group of Mediterranean countries, ∼35 mutations have been reported thus far; however, allele frequencies vary among countries.β-Thal is a major public health concern in Turkey; throughout the country the gene frequency is estimated to be 2.1%, but in certain regions, this figure increases to 10%. The estimated number of carriers is 1,300,000 and the number of homozygous β-thal patients is around 4,000. The number of affected births is higher than expected, since the birthrate is still very high in Turkey, and the number of consanguineous marriages is above 60% in the eastern parts of the country. Unlike many other Mediterranean countries, β-thal in Turkey is very heterogeneous at the clinical level, transfusion-dependent β-thal major predominating. Between 1987 and 2006, more than 1,500 patients with homozyous β-thal, unrelated and not preselected, were investigated by DNA analysis. Our results revealed that by far the most common mutation in Turkey is IVS-I-110 (G→A), followed by IVS-I-6 (T→C) and frameshift codon (FSC) 8 (−AA). The six most common mutations add up to ∼70.3%, and the overall frequency of the first 12 mutations is 83.3%. The ratio of β 0:β +-thal mutations is 1:1, but the majority of β +-thal cases carry the severe IVS-I-110 lesion; thus, most of these mutations give rise to β-thal major in homozygous or compound heterozygous combinations. In addition to the 12 common mutations, several rare and four novel β-thal mutations were reported in the framework of this project, totaling 36 mutations. Turkey's large molecular heterogeneity can be explained by its unique geographical position and rich history, an important crossroad between cultures, civilizations and continents for several centuries. This study shows that despite its great molecular heterogeneity, and with the advent of polymerase chain reaction (PCR)-based techniques and improved methods of early fetal sampling, heterozygote screening and prenatal diagnosis are feasible in Turkey.