Beta-thalassaemia intermedia due to a complex alpha-globin rearrangement and a heterozygous beta thalassaemia mutation.

Publisher: Wiley-Blackwell Country of Publication: England NLM ID: 0372544 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1365-2141 (Electronic) Linking ISSN: 00071048 NLM ISO Abbreviation: Br J Haematol Subsets: MEDLINE

Publication: Oxford : Wiley-Blackwell
Original Publication: Oxford : Blackwell Scientific Publications

beta-Thalassemia*/genetics ; alpha-Globins*/genetics ; Heterozygote* ; Mutation*; Humans ; Female ; Gene Rearrangement ; Child

The alpha-thalassaemia alleles are very frequent in the world's population. The main molecular mechanism is a large deletion with the loss of one or two alpha genes. Another type of rarer abnormality exists: the gain of alpha genes. The consequence of a gain is an overproduction of alpha-globin chains, which aggravates a beta-thalassaemia trait into an intermedia phenotype (non-transfusion-dependent thalassaemia, NTDT). Here, we report the case of a young girl referred for a beta-NTDT with a combination never described in the literature: a heterozygous beta-thalassaemia mutation associated with a copy number gain of the alpha-globin locus and -alpha 3.7 deletion on the same allele.
(© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Piel FB, Weatherall DJ. The α‐thalassemias. N Engl J Med. 2014;371(20):1908–1916.
Goossens M, Dozy AM, Embury SH, Zachariades Z, Hadjiminas MG, Stamatoyannopoulos G, et al. Triplicated alpha‐globin loci in humans. Proc Natl Acad Sci USA. 1980;77(1):518–521.
Galanello R, Ruggeri R, Paglietti E, Addis M, Melis MA, Cao A. A family with segregating triplicated alpha globin loci and beta thalassemia. Blood. 1983;62(5):1035–1040.
Camaschella C, Kattamis AC, Petroni D, Roetto A, Sivera P, Sbaiz L, et al. Different hematological phenotypes caused by the interaction of triplicated alpha‐globin genes and heterozygous beta‐thalassemia. Am J Hematol. 1997;55(2):83–88.
Traeger‐Synodinos J, Kanavakis E, Vrettou C, Maragoudaki E, Michael T, Metaxotou‐Mavromati A, et al. The triplicated alpha‐globin gene locus in beta‐thalassaemia heterozygotes: clinical, haematological, biosynthetic and molecular studies. Br J Haematol. 1996;95(3):467–471.
Oron V, Filon D, Oppenheim A, Rund D. Severe thalassaemia intermedia caused by interaction of homozygosity for alpha‐globin gene triplication with heterozygosity for beta zero‐thalassaemia. Br J Haematol. 1994;86(2):377–379.
Harteveld CL, Refaldi C, Cassinerio E, Cappellini MD, Giordano PC. Segmental duplications involving the alpha‐globin gene cluster are causing beta‐thalassemia intermedia phenotypes in beta‐thalassemia heterozygous patients. Blood Cells Mol Dis. 2008;40:312–316.
Pang D, Shang X, Cai D, Zhu F, Cheng Y, Zhong J, et al. Thalassaemia intermedia caused by coinheritance of a β‐thalassaemia mutation and a de novo duplication of α‐globin genes in the paternal allele. Br J Haematol. 2019;186(4):620–624.
Clark B, Shooter C, Smith F, Brawand D, Steedman L, Oakley M, et al. Beta thalassaemia intermedia due to co‐inheritance of three unique alpha globin cluster duplications characterised by next generation sequencing analysis. Br J Haematol. 2018;180(1):160–164.
Jiang H, Liu S, Zhang YL, Wan JH, Li R, Li DZ. Association of an α‐globin gene cluster duplication and heterozygous β‐thalassemia in a patient with a severe thalassemia syndrome. Hemoglobin. 2015;39(2):102–106.
Farashi S, Vakili S, Faramarzi Garous N, Ashki M, Imanian H, Azarkeivan A, et al. Copy number variations of six and seven α‐globin genes in a family with intermedia and major thalassemia phenotypes. Expert Rev Hematol. 2015;8(5):693–698.
Sollaino MC, Paglietti ME, Perseu L, Giagu N, Loi D, Galanello R. Association of α globin gene quadruplication and heterozygous β thalassemia in patients with thalassemia intermedia. Haematologica. 2009;94(10):1445–1448.
Huang W, Qu S, Qin Q, Yang X, Han W, Lai Y, et al. Nanopore third‐generation sequencing for comprehensive analysis of hemoglobinopathy variants. Clin Chem. 2023;69(9):1062–1071.
Colosimo A, Gatta V, Guida V, Leodori E, Foglietta E, Rinaldi S, et al. Application of MLPA assay to characterize unsolved α‐globin gene rearrangements. Blood Cells Mol Dis. 2011;46(2):139–144.

Keywords: diagnostic haematology; haemoglobinopathies; haemolytic anaemia

0 (alpha-Globins)

Date Created: 20240819 Date Completed: 20241116 Latest Revision: 20241118

20241119

10.1111/bjh.19715

39155476