TY - JOUR
T1 - Genetic analysis of β-thalassemia intermedia in Israel
T2 - Diversity of mechanisms and unpredictability of phenotype
AU - Rund, Deborah
AU - Oron-Karni, Varda
AU - Filon, Dvora
AU - Goldfarb, Ada
AU - Rachmilewitz, Eliezer
AU - Oppenheim, Ariella
PY - 1997
Y1 - 1997
N2 - Molecular analysis was performed on 95 Israeli patients with thalassemia intermedia, representing 60 families of Arab (Moslem and Christian), Jewish, Druze, and Samaritan origin. There was a wide range of phenotypic severity, with baseline hemoglobin levels ranging from 5.5 to 10.7. Eighteen thalassemia mutations were found (29 genotypes), which were subdivided into groups, according to the severity of mutations. A consistently mild phenotype (10 families) was caused by compound heterozygosity for a silent mutation, such as -101 C-T or by coexistence of triplicated α-globin genes with thalassemia trait. In 39 thalassemia intermedia families, the genotype which was found was one which led to severe thalassemia intermedia, or, in other families, was associated with thalassemia major. Elevated hemoglobin F ameliorated the disease in some patients with a severe genotype. We did not find a beneficial effect of concurrent α-thalassemia in any of the families studied. In 11 families, only one β-thalassemia allele was identified. One was a dominant thalassemia intermedia allele. Three additional families with heterozygous β-thalassemia had excess α-globin genes (5 or 6 total). In 7 of these heterozygotes, no explanation was found for the thalassemia intermedia phenotype. Our results suggest a substantial influence of as yet unknown genetic modifiers. These findings have important implications for prenatal diagnosis and for the genetic counseling of families with thalassemia intermedia.
AB - Molecular analysis was performed on 95 Israeli patients with thalassemia intermedia, representing 60 families of Arab (Moslem and Christian), Jewish, Druze, and Samaritan origin. There was a wide range of phenotypic severity, with baseline hemoglobin levels ranging from 5.5 to 10.7. Eighteen thalassemia mutations were found (29 genotypes), which were subdivided into groups, according to the severity of mutations. A consistently mild phenotype (10 families) was caused by compound heterozygosity for a silent mutation, such as -101 C-T or by coexistence of triplicated α-globin genes with thalassemia trait. In 39 thalassemia intermedia families, the genotype which was found was one which led to severe thalassemia intermedia, or, in other families, was associated with thalassemia major. Elevated hemoglobin F ameliorated the disease in some patients with a severe genotype. We did not find a beneficial effect of concurrent α-thalassemia in any of the families studied. In 11 families, only one β-thalassemia allele was identified. One was a dominant thalassemia intermedia allele. Three additional families with heterozygous β-thalassemia had excess α-globin genes (5 or 6 total). In 7 of these heterozygotes, no explanation was found for the thalassemia intermedia phenotype. Our results suggest a substantial influence of as yet unknown genetic modifiers. These findings have important implications for prenatal diagnosis and for the genetic counseling of families with thalassemia intermedia.
KW - Genetic counseling
KW - Genetic modifiers
KW - Genotype/phenotype
KW - Mutations
KW - Thalassemia intermedia
UR - http://www.scopus.com/inward/record.url?scp=0031012244&partnerID=8YFLogxK
U2 - 10.1002/(SICI)1096-8652(199701)54:1<16::AID-AJH3>3.0.CO;2-7
DO - 10.1002/(SICI)1096-8652(199701)54:1<16::AID-AJH3>3.0.CO;2-7
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C2 - 8980256
AN - SCOPUS:0031012244
SN - 0361-8609
VL - 54
SP - 16
EP - 22
JO - American Journal of Hematology
JF - American Journal of Hematology
IS - 1
ER -