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, c aused primarily by gene deletions. In Israel, where alpha(o)-trait thalasse mia is uncommon, It is of particular importance because of its phenotypic I nteractions with beta-thalassemia in hetero- and homozygotes. In a study of 232 individuals referred for molecular evaluation of anemia, 303 chromosom es carried alpha-globin gene abnormalities; 6 gene rearrangements and 11 po int mutations were identified. This unexpected heterogeneity is in part due to the many ethnic subgroups represented by these patients. Our findings i nclude nine unique Israeli alleles, 3 of which are described here for the f irst time. An equal number of point mutations was found in the alpha 2-glob in gene as compared to alpha 1. A threonine deletion in codon 39 of the alp ha 1-globin gene, found frequently in Arabs, is unique to Israel and probab ly represents one of several indigenous alleles. Among Arabs, point mutatio ns were more frequent than large deletions. Surprisingly, in Ashkenazi Jews , who resided for many centuries in a nonmalarial environment, a single alp ha-globin gene deletion -alpha(3.7) was found in many cases. The clinical p resentation of individuals carrying two or more alpha-globin lesions was hi ghly variable. In general, the severity correlated inversely with the numbe r of functional alpha-globin genes. In some cases, Impairment of two alpha- globin genes by point mutations led to a thalassemia-intermedia-like pictur e which could be misdiagnosed as beta-thalassemia. We conclude that alpha-t halassemia is phenotypically and genotypically more heterogeneous than prev iously recognized. DNA analysis Is Invaluable as it provides a specific dia gnosis and enables reliable genetic counseling. (C) 2000 Wiley-Liss, Inc.