I-b.   Deletional Beta-Thalassemia Alleles

At present (April, 1997) 17 different beta-thal alleles have been discovered which are characterized by a (partial) deletion of the beta-globin gene. Details about these abnormalities can be found on pages 141 through 151. The sizes of the eight smallest deletions (25 bp through 1,605 bp) are shown in Fig. 3; the 3' and 5' endpoints of each of these have been determined and are listed in the figure. The nine larger deletions are depicted in Fig. 4; for all but one (the 4,237 bp Czech deletion) the deletion includes the entire beta-globin gene. These abnormalities are rare occurrences with the exception of the 619 bp deletion which is observed at high frequencies in Indian and some Southeast Asian populations (see Table XI-a and Table XI-b on pages 163 and 164). The 25 bp deletion is observed in quite a few families in Middle Eastern countries.

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FIG. 3. The sizes and locations of eight deletions of 25 to 1,605 bp of DNA involving part of the beta-globin gene.

Heterozygotes for many of these deletions have unusually high levels of Hb A2, particularly when calculated as percent of adult Hbs A and A2. The authors found data for heterozygotes of 14 of the 17 different deletions, either in their own files or in published papers (46 carriers); no information was available for the -44 bp and the -105 bp deletions, and the ~67 kb Italian deletion. It has been suggested that markedly elevated levels of Hb A2 in heterozygotes are due to the removal of the beta-globin gene promoter, thus eliminating the competition of the beta and delta promoter sequences for transacting factors and increasing the expression of the delta-globin gene (1-3). A review of the data listed in Fig. 5 supports this concept. Hb A2 levels were found to be in excess of 6% except for type 1 and type 6 (in both the beta-globin gene promoter is intact) and surprisingly, in type 15 (the SEA deletion). Thein (3) has suggested that a similar mechanism can be responsible for the (slight) increase in Hb F level seen in most of these beta-thal heterozygotes; it is indeed worth noting that homozygotes for some of these deletions (the Dutch deletion of 12,620 bp and the Asian Indian 10,329 bp deletion) have 97-98% Hb F and 2-3% Hb A2, and do not require blood transfusions.

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FIG. 4. The sizes and location of nine deletions of 3 kb or more involving part of or the entire beta-globin gene.

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FIG. 5. The levels of Hb A2 in 46 heterozygotes for different deletional beta-thal alleles; the numbers 1-14 refer to the types listed in Figs. 3 and 4.

1. Codrington, J.F., Li, H-W., Kutlar, F., Gu, L-H., Ramachandran, M., and Huisman, T.H.J.: Blood, 76:1246, 1990.
2. Huisman, T.H.J.: Acta Haematol., in press, 1997.
3. Thein, S.L.: in The Haemoglobinopathies, edited by D.J. Weatherall and D.R. Higgs, Bailliére's Clinical Haematology, Vol. 6, page 151, W.B. Saunders Company, London, 1993.

This material is from the book A Syllabus of Thalassemia Mutations (1997) by Titus H.J. Huisman, Marianne F.H. Carver, and Erol Baysal, published by The Sickle Cell Anemia Foundation in Augusta, GA, USA. Copyright © 1997 by Titus H.J. Huisman. All rights reserved. Neither this work nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, microfilming and recording, or by any information storage and retrieval systems, without permission in writing from the Author.