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Diversity of alpha-globin mutations and clinical presentation of alpha-thalassemia in Israel.

Alpha-thalassemia is among the world's most common single gene disorders, caused primarily by gene deletions. In Israel, where alpha(o)-trait thalassemia is uncommon, it is of particular importance because of its phenotypic interactions with beta-thalassemia in hetero- and homozygotes. In a study of 232 individuals referred for molecular evaluation of anemia, 303 chromosomes carried alpha-globin gene abnormalities; 6 gene rearrangements and 11 point mutations were identified. This unexpected heterogeneity is in part due to the many ethnic subgroups represented by these patients. Our findings include nine unique Israeli alleles, 3 of which are described here for the first time. An equal number of point mutations was found in the alpha2-globin gene as compared to alpha1. A threonine deletion in codon 39 of the alpha1-globin gene, found frequently in Arabs, is unique to Israel and probably represents one of several indigenous alleles. Among Arabs, point mutations were more frequent than large deletions. Surprisingly, in Ashkenazi Jews, who resided for many centuries in a nonmalarial environment, a single alpha-globin gene deletion -alpha(3.7) was found in many cases. The clinical presentation of individuals carrying two or more alpha-globin lesions was highly variable. In general, the severity correlated inversely with the number of functional alpha-globin genes. In some cases, impairment of two alpha-globin genes by point mutations led to a thalassemia-intermedia-like picture which could be misdiagnosed as beta-thalassemia. We conclude that alpha-thalassemia is phenotypically and genotypically more heterogeneous than previously recognized. DNA analysis is invaluable as it provides a specific diagnosis and enables reliable genetic counseling.