Diversity of α‐globin mutations and clinical presentation of α‐thalassemia in Israel

α-Thalassemia is among the world's most common single gene disorders, caused primarily by gene deletions. In Israel, where αo-trait thalassemia is uncommon, it is of particular importance because of its phenotypic interactions with β-thalassemia in hetero- and homozygotes. In a study of 232 individuals referred for molecular evaluation of anemia, 303 chromosomes carried α-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 α2-globin gene as compared to α1. A threonine deletion in codon 39 of the α1-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 α-globin gene deletion −α3.7 was found in many cases. The clinical presentation of individuals carrying two or more α-globin lesions was highly variable. In general, the severity correlated inversely with the number of functional α-globin genes. In some cases, impairment of two α-globin genes by point mutations led to a thalassemia-intermedia-like picture which could be misdiagnosed as β-thalassemia. We conclude that α-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. Am. J. Hematol. 65:196–203, 2000.© 2000 Wiley-Liss, Inc.