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Single-Tube Multiplex-PCR Screen for Anti-3.7 and Anti-4.2 -Globin Gene Triplications

Departments of
¹ Pediatrics and
² Obstetrics & Gynecology, National University of Singapore, Singapore 119074, Singapore
³ The Children’s Medical Institute and Molecular Diagnosis Center, Department of Laboratory Medicine, National University Hospital, Singapore 119074, Singapore

⁴ Departments of Pediatrics and Gynecology & Obstetrics, The Johns Hopkins University School of Medicine, Baltimore, MD 21287

⁵ Division of Hematology, Department of Pathology, The University of Hong Kong and Queen Mary Hospital, Hong Kong, People’s Republic of China

⁶ Departments of Medicine and Pathology, Boston University School of Medicine, Boston, MA 02118

⁷ The Western Australian Centre for Pathology and Medical Research, Nedlands, WA 6009, Australia

^aaddress correspondence to this author at: Department of Pediatrics, National University of Singapore, Level 4, National University Hospital, 5 Lower Kent Ridge Road, Singapore 119074, Singapore; fax 65-6779-7486, e-mail paecs@nus.edu.sg

The first 20% of the full text of this article appears below.

The coexistence of -globin gene triplication () is an important modulator of the severity of ß-thalassemia trait or ß-thalassemia intermedia, exacerbating the phenotypic severity of ß-thalassemia by causing more globin chain imbalance (1)(2). Typically, the inheritance of a single ß-thalassemia allele is associated with mild anemia and hypochromic microcytic red cells. Compared with simple ß-heterozygotes, co-inheritance of triplicated or quadruplicated -globin genes in ß-heterozygotes often leads to more significant anemia, splenomegaly, more pronounced red cell abnormalities, the presence of circulating normoblasts, higher hemoglobin F concentrations, and even the presence of inclusion bodies in erythroblasts (3)(4). Because the - and ß-globin gene clusters are physically unlinked and segregate independently, ß-thalassemia carriers who also carry triplicated or quadruplicated -globin genes have a 25% risk of having a similarly affected offspring, although their partners may be entirely normal.

Triplicated -globin genes appear to be ubiquitous and have been found in most populations (2). They result from misalignment and unequal crossover between the homologous X-, Y-, and Z-box segments of the -globin gene cluster during meiosis (Fig. 1A ). Generally, two types of triplicated alleles can be generated from an unequal crossover, ^anti3.7 and ^anti4.2. If the crossover occurs between the homologous Z2 and Z1 boxes, also referred to as a "rightward crossover", this produces a -^3.7 single-gene deletion allele and the reciprocal ^anti3.7 triplicated allele. However, if the crossover occurs between the X2 and X1 boxes (a "leftward crossover"), a -^4.2 single-gene deletion allele and the reciprocal ^anti4.2 triplicated allele are generated (5).

View larger version (50K): [in this window] [in a new window]   Figure 1. Formation and molecular detection of -globin gene triplications. (A), misalignment and unequal crossover at the -globin gene cluster generates a single gene deletion and reciprocal gene triplication. . . . [Full Text of this Article]

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