Molecular Basis and Prenatal Diagnosis of 9 - Thalassemia By Haig

Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by only. The American The J Society ournal of of Hematology VOL 72, NO 4 OCTOBER 1988 THALASSEMIA is an autosomal recessive disease characterized by hypochromic, hemolytic anemia, and dependence on blood transfusions to sustain life.' Even with chelation therapy to remove excess iron stores, the life expectancy in classic fl-thalassemia major is shortened to 25 to 30 years on average. Those individuals who carry a single /3-thalassemia gene ((-thalassemia trait) are thought to have a selective advantage over normal individuals vis-#{224}-vis ma-larial infection. Thus, the disorder and 3-thalassemia genes are concentrated in peoples residing in regions of the world endemic for malaria, including Mediterraneans, North Afri-cans and Middle Easterners, Asian Indians, Chinese and Southeast Asians, and black Africans. It has been estimated that 3% of the world's population, or 1 50 million people, carry a fl-thalassemia gene. These carriers or individuals with j9-thalassemia trait are essentially normal, although they can usually be detected by screening red cell indices that demonstrate a reduced mean corpuscular volume and reduced mean corpuscular hemoglobin value, followed by the determination of an elevated hemoglobin A2 level. Over the past 8 years the variety of molecular defects in the f3-globin gene that produces fl-thalassemia has been increasingly characterized so that today we estimate that the gene defects that account for 99% of f3-thalassemia genes in the world are known. In fact, j3-thalassemia is the first single gene disorder due to multiple mutations whose molecular basis has been essentially completely characterized. Methods used for prenatal diagnosis of the disease have correspondingly progressed along with our state of knowledge, beginning with studies of fl-chain synthesis, continuing to indirect detection by using DNA polymorphisms, and finally reaching direct detection of mutant alleles. In this review we will update reviews of 1984 on the various /3-thalassemia alleles and on prenatal diagnosis of these alleles.24 was unusually small and simple for a human gene: it is 1.5 kilobases in size and contains only two introns. Another important factor aiding characterization of the fl-thalassemia mutations is the genetics of this disease. In diseases that are X-linked genetic lethals, every unrelated affected individual may have a new allele. Thus, among 200 unrelated hemophiliacs, one might find between 190 and 200 different mutant alleles of the factor VIII gene.9 In contrast, identical fl-thalassemia alleles are found in unrelated families. This observation presumably stems …