Chapter 181

## Abstract

Abstract  McKusick (OMIM) numbers have been assigned to the various globin genes. The entries also document the allelic series that cause the corresponding hemoglobinopathies; the alleles are given numbers after the decimal point. The OMIM numbers are: alpha (α) locus-1 (141800); α locus-2 (141850); beta (B) locus (141900); gamma locus (142200); delta locus (142000); epsilon locus (142100) zeta locus (142310). Three hemoglobin variants that reach polymorphic frequencies in some populations are: HbC (141900.0038); HbE (141900.0071); HbS (141900.0243). HbM variants are numbered by locus and allele (e.g., HbMBOSTON (141800.0092), HbMHYDE PARK (141900.0164). The unstable Hb variants are also an allelic series, e.g., HbZURICH 141900.0310. HbF (Hereditary Persistence of Fetal Hb) (HPFH) is a separate entry (141790); as is HbH-related mental retardation, deletion type (141750).

Abstract  The GenBank accession numbers for the nucleotide sequences of the globin genes are: globin genes, Z84721; β globin genes, UO1317.

Abstract  The most comprehensive website for mutation of β globin genes is http://globin.cse.psu.edu.

Abstract

1. The inherited disorders of hemoglobin fall into three overlapping groups: structural variants; thalassemias characterized by a reduced rate of synthesis of one or more of the globin chains of hemoglobin; and conditions in which fetal hemoglobin synthesis persists beyond the neonatal period, known collectively as hereditary persistence of fetal hemoglobin. Taken together, they are the commonest single-gene disorders in the world population.

2. Because the different hemoglobin disorders co-exist at a high frequency in many populations, and because individuals may inherit more than one type, hemoglobin disorders are responsible for an extremely complex series of clinical phenotypes. Their molecular pathology has been elucidated in many subjects and a start has been made in relating primary molecular defects to associated clinical phenotypes.

3. Although some 750 structural hemoglobin variants have been identified, only three—hemoglobins S, C, and E—reach very high frequencies in some populations. The various interactions of the hemoglobin S gene may result in chronic hemolytic anemia and vasculo-occlusive episodes. Hemoglobin C is associated with a mild hemolytic anemia, while hemoglobin E is synthesized at a reduced rate and results in the phenotype of a mild form of β thalassemia. There are other groups of much rarer variants that are of clinical significance, including the unstable hemoglobins associated with hemolytic anemia, high oxygen affinity variants that cause congenital polycythemia, and variants associated with methemoglobinemia.

4. The β thalassemias are divided into β+ thalassemia, in which some β globin chains are produced, and βo thalassemia in which there is no β chain synthesis. The α thalassemias are similarly divided into αo and α+ thalassemias. Over 170 different mutations have been identified as the cause for β thalassemia, most of which interfere with the transcription of β globin mRNA or its processing or translation. A few types of β thalassemia result from the production of highly unstable β globin chains. The common forms of α thalassemia result from deletions that involve either one or both of the linked α globin genes. Some less common forms of α thalassemia result from point mutations which interfere with the translation or transcription of the α globin genes.

5. The development of rapid methods for studying the globin genes has also made it possible to analyze their population genetics and the mechanisms underlying their high gene frequencies.

6. The carrier states for most of the important hemoglobin disorders are easily identified. Their homozygous or compound heterozygous states can be identified in fetal life by fetal blood sampling or analysis of DNA obtained from chorionic villi. Hence, the disease can be avoided in an affected family by reproductive counseling and a choice of options.

7. Apart from marrow transplantation, there is no definitive treatment, and management is symptomatic.

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