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 ind...

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Veröffentlicht in:American journal of hematology 2000-11, Vol.65 (3), p.196-203
Hauptverfasser: Oron‐Karni, Varda, Filon, Dvora, Shifrin, Yulia, Fried, Elchanan, Pogrebijsky, Galina, Oppenheim, Ariella, Rund, Deborah
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container_start_page 196
container_title American journal of hematology
container_volume 65
creator Oron‐Karni, Varda
Filon, Dvora
Shifrin, Yulia
Fried, Elchanan
Pogrebijsky, Galina
Oppenheim, Ariella
Rund, Deborah
description 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.
doi_str_mv 10.1002/1096-8652(200011)65:3<196::AID-AJH4>3.0.CO;2-8
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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. 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subjects alpha-Thalassemia - epidemiology
alpha-Thalassemia - genetics
Anemias. Hemoglobinopathies
Biological and medical sciences
Diseases of red blood cells
Ethnic Groups
genetic disease
Genetic Variation
Genotype
Globins - genetics
Hematologic and hematopoietic diseases
Humans
Israel - epidemiology
malarial selection
Medical sciences
molecular genetics
Phenotype
phenotype–genotype
Point Mutation
α‐thalassemia
title Diversity of α‐globin mutations and clinical presentation of α‐thalassemia in Israel
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