Hemoglobinopathies in Iran: An Updated Review

  • Abolfazl Nasiri Students Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran. AND Department of Clinical Biochemistry, Kermanshah University of Medical Sciences, Kermanshah, Iran
  • Zohreh Rahimi Mail Department of Clinical Biochemistry, Kermanshah University of Medical Sciences, Kermanshah, Iran. AND Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
  • Asad Vaisi-Raygani Department of Clinical Biochemistry, Kermanshah University of Medical Sciences, Kermanshah, Iran. AND Fertility and Infertility Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
Hemoglobinopathies; Thalassemia, HbS, HbD, Mutation


Hemoglobinopathies are the most common single gene disorders (monogenic disorders) in the world population.  Due to specific position of Iran and the presence of multi-ethnic groups in the country, there are many varieties in the molecular genetics and clinical features of hemoglobinopathies in Iran. Hemoglobinopathies include structural variants, thalassemias, and hereditary persistence of fetal hemoglobin. In this review, we look at the common structural variants in various parts of the country along with their hematological and clinical characteristics. Also, we discuss about the burden of the thalassemias in the country, different types, complications, molecular defects and therapy.


1. Scriver CR, Beaudet AL, Sly WS, et al. The Metabolic and Molecular Bases of Inherited Disease, Montreal McGraw-Hill; 2001; 24(1):45-52.
2. Weatherall D. Current trends in the diagnosis and management of haemoglobinopathies. Scand J Clin Lab Invest. 2007; 67(1):1-2.
3. Rahimi Z. Genetic epidemiology, hematological and clinical features of hemoglobinopathies in Iran. BioMed Res Int. 2013; 2013:1-10.
4. Acquaye JK, Omer A, Ganeshaguru K, et al. Non‐benign sickle cell anaemia in western Saudi Arabia. Br J Haematol. 1985; 60(1):99-108.
5. Adekile A, Haider M. Morbidity, βS haplotype and α-globin gene patterns among sickle cell anemia patients in Kuwait. Acta Haematol. 1996; 96(3):150-4.
6. Adekile A. Historical and anthropological correlates of βS haplotypes and α-and β-thalassemia alleles in the Arabian Peninsula. Hemoglobin. 1997; 21(3):281-96.
7. Al Arrayed SS, Haites N. Features of sickle-cell disease in Bahrain. 1995; 12(4):41-48.
8. Zamani S, Borhan Haghighi A, Haghpanah S, et al. Transcranial Doppler Screening in 50 Patients With Sickle Cell Hemoglobinopathies in Iran. J Pediatr Hematol Oncol. 2017; 39(7):506-512.
9. Alsultan A, Aleem A, Ghabbour H, et al. Sickle cell disease subphenotypes in patients from Southwestern Province of Saudi Arabia. J Pediatr Hematol Oncol. 2012; 34(2):79-84.
10. Haghshenass M, Ismail-Beigi F, Clegg J, et al. Mild sickle-cell anaemia in Iran associated with high levels of fetal haemoglobin. J Med Genet. 1977; 14(3):168-171.
11. Habibzadeh F, Yadollahie M, Ayatollahie M, et al. The prevalence of sickle cell syndrome in south of Iran. Iran J Med Sci. 1999;24:32-4.
12. Rahgozar S, Poorfathollah AA, Moafi AR, et al. βS gene in Central Iran is in linkage disequilibrium with the Indian–Arab haplotype. Am J Hematol. 2000; 65(3):192-195.
13. Booth C, Inusa B, Obaro SK. Infection in sickle cell disease: a review. Int J Infect Dis. 2010; 14(1):e2-e12.
14. Keikhaei B, Mohseni AR, Norouzirad R, A, et al. Altered levels of pro-inflammatory cytokines in sickle cell disease patients during vaso-occlusive crises and the steady state condition. Eur Cytokine Netw. 2013; 24(1):45-52.
15. Shahripour RB, Mortazavi MM, Barlinn K, et al. Can stop trial velocity criteria be applied to Iranian children with sickle cell disease? J stroke. 2014; 16(2):97-101.
16. Green NS, Barral S. Emerging science of hydroxyurea therapy for pediatric sickle cell disease. Pediatr Res. 2014; 75(0):196-204.
17. Keikhaei B, Yousefi H, Bahadoram M. Hydroxyurea: Clinical and hematological effects in patients with sickle cell anemia. Glob J Health Sci. 2016; 8(3):252-256.
18. Rahimi Z, Merat A, Gerard N, et al. Implications of the genetic epidemiology of globin haplotypes linked to the sickle cell gene in southern Iran. Hum Biol. 2006:78 (6):719-31.
19. Rusanova I, Cossio G, Moreno B, et al. β‐globin gene cluster haplotypes in sickle cell patients from Panamá. Am J Hum Biol. 2011; 23(3):377-80.
20. Rahimi Z, Karimi M, Haghshenass M, et al. β‐Globin gene cluster haplotypes in sickle cell patients from southwest Iran. Am J Hematol. 2003;74(3):156-60.
21. Rahimi Z, Vaisi-Raygani A, Merat A, et al. Level of hemoglobin F and Gg gene expression in sickle cell disease and their association with haplotype and XmnI polymorphic site in South of Iran. Iran J Med Sci. 2007; 32(4):234-239.
22. Rahimi Z, Muniz A, Mozafari H. Abnormal hemoglobins among Kurdish population of Western Iran: hematological and molecular features. Mol Biol Rep. 2010; 37(1):51-7.
23. Rahimi Z, Akramipour R, Nagel RL, et al. The β-globin gene haplotypes associated with Hb D-Los Angeles [β121 (GH4) Glu→ Gln] in western Iran. Hemoglobin. 2006;30(1):39-44.
24. Galehdari H, Salehi B, Azmoun S, et al. Comprehensive spectrum of the β-thalassemia mutations in Khuzestan, Southwest Iran. Hemoglobin. 2010;34(5):461-68.
25. Bunn HF, Forget BG. Hemoglobin: molecular, genetic, and clinical aspects. WB Saunders Co.; 1986; 35(1):26-54.
26. Aghdashloo BE, Khmenini O, Shohreh P. Co-legacy against 3.7 triplication with hemoglobin D/0 thalassemia: A case report from South west of Iran. Int J Genet. Genomics. 2015;2 (3):080-084
27. Yavarian M, Karimi M, Paran F, et al. Multi Centric Origin of Hb D-Punjab [β121 (GH4) Glu→ Gln, G AA> C AA]. Hemoglobin. 2009;33(6):399-405.
28. Mahdavi MR, Jalali H, Kosaryan M, et al. β-Globin gene cluster haplotypes of Hb D-Los Angeles in Mazandaran province, Iran. Genes Genet Syst. 2015; 90(1):55-57.
29. Lorkin P, Charlesworth D, Lehmann H, et al. Two haemoglobins Q, α74 (EF3) and α75 (EF4) Aspartic acid→ Histidine. Br J Haematol. 1970; 19(1):117-125.
30. Aksoy M, Gurgey A, Altay C, et al. Some notes about Hb Q-India and Hb Q-Iran. Hemoglobin. 1986; 10(2):215-9.
31. Khorshidi M, Roshan P, Bayat N, et al. Hemoglobin Q-Iran detected in family members from Northern Iran: a case report. J Med Case Reports. 2012; 6: 47.
32. Rahimi Z, Akramipour R, Vaisi-Raygani A, et al. An Iranian Child With HbQ-Iran [α75 (EF4) Asp→ His]/− α3. 7 kb/IVSII. 1 G→ A: First Report. J Pediatr Hematol Oncol. 2007; 29(9):649-651.
33. Rahimi Z, Rezaei M, Nagel RL, Muniz A. Molecular and hematologic analysis of hemoglobin Q-Iran and hemoglobin Setif in Iranian families. Arch Iran Med. 2008;11(4):382-6.
34. Nozari G, Ralthar S, Darbre P, et al. Hemoglobin Setif (α94 (G1) ASP→ TYR) in Iran a report of 9 Cases. Hemoglobin. 1977; 1(3):289-292.
35. Farashi S, Garous NF, Vakili S, et al. Characterization of homozygous Hb Setif (HBA2: c. 283G> T) in the Iranian population. Hemoglobin. 2016;40(1):53-55.
36. Keikhaei B, Slehi-fard P, Shariati G, Khosravi A. Genetics of Iranian Alpha-Thalassemia Patients: A Comprehensive Original Study. Biochem. Genet. 2018:1-16.
37. Hafezi-Nejad N, Khosravi M, Bayat N, Kariminejad A, Hadavi V, Oberkanins C, et al. Characterizing a cohort of α-thalassemia couples collected during screening for hemoglobinopathies: 14 years of an iranian experience. Hemoglobin. 2014;38(3):153-57.
38. Abolghasemi H, Amid A, Zeinali S, Radfar MH, Eshghi P, Rahiminejad MS, et al. Thalassemia in Iran: epidemiology, prevention, and management. J. Pediatr. Hematol./Oncol. 2007;29(4):233-38.
39. Bilgen T, Clark O, Ozturk Z, Akif Yesilipek M, Keser I. Two novel mutations in the 3′ untranslated region of the beta‐globin gene that are associated with the mild phenotype of beta thalassemia. Int. J. Lab. Hematol. 2013;35(1):26-30.
40. Patrinos GP, Kollia P, Papadakis MN. Molecular diagnosis of inherited disorders: lessons from hemoglobinopathies. Hum. Mutat. 2005;26(5):399-412.
41. Mentzer WC, Kan YW. Prospects for research in hematologic disorders: sickle cell disease and thalassemia. JAMA. 2001; 285(5):640-2.
42. Alizadeh S, Bavarsad MS, Dorgalaleh A, et al. Frequency of beta-thalassemia or beta-hemoglobinopathy carriers simultaneously affected with alpha-thalassemia in Iran. Clin Lab. 2014; 60(6):941-9.
43. Strauss BS. Genetic counseling for thalassemia in the Islamic Republic of Iran. Perspect Biol Med. 2009; 52(3):364-76.
44. Asadi S, Habibi S, Nazirzadeh A. Assessment of beta-globin gene mutations in patients with beta-thalassemia created in the Chain, the population of the city of Tabriz in Iran. World J Pharm Pharm Sci. 2016; 5(1):343-362
45. Hashemi-Soteh MB, Mousavi SS, Tafazoli A. Haplotypes inside the beta-globin gene: use as new biomarkers for beta-thalassemia prenatal diagnosis in north of Iran. J Biomed Sci. 2017; 24(1):92.
46. Jaripour ME, Hayatigolkhatmi K, Iranmanesh V, et al. Prevalence of β-thalassemia mutations among Northeastern Iranian population and their impacts on hematological indices and application of prenatal diagnosis, a seven-year study. Mediterr J Hematol Infect Dis. 2018; 10(1): e2018042.
47. Moghadam M, Karimi M, Dehghani SJ, et al. Effectiveness of β‐thalassemia prenatal diagnosis in Southern Iran: a cohort study. Prenatal Diagn. 2015;35(12):1238-42.
48. Miri‐Moghaddam E, Zadeh‐Vakili A, Rouhani Z, et al. Molecular basis and prenatal diagnosis of β‐thalassemia among Balouch population in Iran. Prenatal Diagn. 2011;31(8):788-91.
49. Saleh-Gohari N, Bazrafshani M. Distribution of β-globin gene mutations in thalassemia minor population of Kerman Province, Iran. Iran J Public Health. 2010; 39(2):69-76.
50. Najmabadi H, Karimi-Nejad R, Sahebjam S, et al. The β-thalassemia mutation spectrum in the Iranian population. Hemoglobin. 2001; 25(3):285-296.
51. Rahimi Z, Muniz A, Parsian A. Detection of responsible mutations for beta thalassemia in the Kermanshah Province of Iran using PCR-based techniques. Mol Biol Rep. 2010; 37(1):149-54.
52. Haghi M, Khorshidi S, Hosseinpour Feizi MA, et al. β-Thalassemia mutations in the Iranian Kurdish population of Kurdistan and West Azerbaijan provinces. Hemoglobin. 2009;33(2):109-14.
53. Galanello R, Origa R. Beta-thalassemia. Orphanet J Rare Dis. 2010; 5:11.
54. El-Beshlawy A, Seoud H, Ibrahim A, et al. Apoptosis in thalassemia major reduced by a butyrate derivative. Acta Haematol. 2005; 114(3):155-9.
55. Vasileiadis I, Roditis P, Dimopoulos S, et al. Impaired oxygen kinetics in beta‐thalassaemia major patients. Acta Physiol (Oxf). 2009; 196(3):357-63.
56. Borgna-Pignatti C, Rugolotto S, De Stefano P, et al. Survival and complications in patients with thalassemia major treated with transfusion and deferoxamine. haematologica. 2004;89(10):1187-93.
57. Toptas B, Baykal A, Yesilipek A, et al. L-carnitine deficiency and red blood cell mechanical impairment in β-thalassemia major. Clin Hemorheol Microcirc. 2006;35(3):349-57.
58. Tabei SMB, Mazloom M, Shahriari M, et al. Determining and surveying the role of carnitine and folic acid to decrease fatigue in β-thalassemia minor subjects. Pediatr Hematol Oncol. 2013; 30(8):742-7.
59. Rund D, Rachmilewitz E. Beta-Thalassemia. N Engl J Med. 2005; 353(11):1135-46.
60. Taher A, Isma'eel H, Cappellini MD. Thalassemia intermedia: revisited. Blood Cells Mol Dis. 2006; 37(1):12-20.
61. Camaschella C, Cappellini MD. Thalassemia intermedia. haematologica. 1995;80(1):58-68.
62. Weatherall D. Thalassemia intermedia: cellular and molecular aspects. J Hematol. 2001;86(1):186-188.
63. Haghpanah S, Vahdati S, Karimi M. Comparison of quality of life in patients with β-Thalassemia intermedia and β-Thalassemia major in Southern Iran. Hemoglobin. 2017; 41(3):169-174.
64. Lal A, Vichinsky E. The role of fetal hemoglobin–enhancing agents in thalassemia. Semi hematol; ; 27(3):241-5.
65. Karimi M, Darzi H, Yavarian M. Hematologic and clinical responses of thalassemia intermedia patients to hydroxyurea during 6 years of therapy in Iran. J Pediatr Hematol Oncol. 2005; 27(7):380-5.
66. Piga A, Perrotta S, Gamberini MR, et al. Luspatercept (ACE-536) reduces disease burden, including anemia, iron overload, and leg ulcers, in adults with beta-thalassemia: results from a phase 2 study. Blood. 2015; 126 (23): 752.
67. Carrancio S, Markovics J, Wong P, et al. An activin receptor II A ligand trap promotes erythropoiesis resulting in a rapid induction of red blood cells and haemoglobin. Br J Haematol. 2014; 165(6):870-82.
68. Karimi M, Borzouee M, Mehrabani A, et al. Echocardiographic finding in beta‐thalassemia intermedia and major: absence of pulmonary hypertension following hydroxyurea treatment in beta‐thalassemia intermedia. Eur J Haematol. 2009; 82(3):213-8.
69. Karimi M, Musallam KM, Cappellini MD, et al. Risk factors for pulmonary hypertension in patients with β thalassemia intermedia. Eur J Intern Med. 2011; 22(6):607-10.
70. Karimi M, Zarei T, Haghpanah S, et al. Relationship Between Some Single-nucleotide Polymorphism and Response to Hydroxyurea Therapy in Iranian patients with β-thalassemia intermedia. J Pediatr Hematol Oncol. 2017; 39(4):e171-e176.
71. Khezri HD, Salehifar E, Kosaryan M, et al. Potential effects of silymarin and its flavonolignan components in patients with β-Thalassemia major: a comprehensive review in 2015. Adv Pharmacol Sci. 2016; 2016: 3046373
72. Gharagozloo M, Moayedi B, Zakerinia M, et al. Combined therapy of silymarin and desferrioxamine in patients with β‐thalassemia major: a randomized double‐blind clinical trial. Fundam Clin Pharmacol. 2009; 23(3):359-65.
73. Hagag AA, Elfaragy MS, Elrifaey SM, et al. Therapeutic value of combined therapy with Deferiprone and Silymarin as iron chelators in Egyptian Children with Beta Thalassemia major. Infect Disord Drug Targets. 2015; 15(3):189-95.
74. Moayedi Esfahani BA, Reisi N, Mirmoghtadaei M. Evaluating the safety and efficacy of silymarin in β-thalassemia patients: a review. Hemoglobin. 2015; 39(2):75-80.
75. Darvishi‐Khezri H, Salehifar E, Kosaryan M, et al. Iron‐chelating effect of silymarin in patients with β‐thalassemia major: A crossover randomised control trial. Phytother Res. 2018; 32(3):496-503.
76. Hojjati MT, Azarkeivan A, Pourfathollah AA, et al. Comparison of MicroRNAs Mediated in Reactivation of the γ-Globin in β-Thalassemia Patients, Responders and Non-Responders to Hydroxyurea. Hemoglobin. 2017; 41(2):110-115.
77. Joulaei H, Shahbazi M, Nazemzadegan B, et al. The diminishing trend of β-thalassemia in Southern Iran from 1997 to 2011: the impact of preventive strategies. Hemoglobin. 2014 ; 38(1):19-23.
78. Ranjbaran R, Okhovat MA, Mobarhanfard A, et al. Analysis of β/α globin ratio by using relative qRT‐PCR for diagnosis of beta‐thalassemia carriers. J Clin Lab Anal. 2013; 27(4):267-71.
79. Zafari M, Gill P, Kowsaryan M, et al. High-resolution melting analysis for noninvasive prenatal diagnosis of IVS-II-I (GA) fetal DNA in minor beta-thalassemia mothers. J Matern Fetal Neonatal Med. 2016; 29(20):3323-8.
80. Giardine B, Borg J, Viennas E, et al. Updates of the HbVar database of human hemoglobin variants and thalassemia mutations. Nucleic Acids Res. 2014; 42(Database issue): D1063–D1069.
81. Weatherall DJ, Clegg JB. Thalassemia-a global health problem. Nat Med. 1996; 2(8):847-9.
82. Zaino EC, Tien YY. Hemoglobinopathy and thalassemia in China. N Engl J Med. 1981; 305(13):766.
83. Kulozik AE, Kar BC, Serjeant GR, et al. The molecular basis of alpha thalassemia in India. Its interaction with the sickle cell gene. Blood. 1988;71(2):467-72.
84. Vichinsky EP. Changing patterns of thalassemia worldwide. Ann N Y Acad Sci. 2005; 1054:18-24.
85. Weatherall D. The inherited disorders of haemoglobin: an increasingly neglected global health burden. Indian J Med Res. 2011; 134(4): 493–497.
86. Najmabadi H, Pourfathollah AA, Neishabury M, et al. Rare and unexpected mutations among Iranian beta-thalassemia patients and prenatal samples discovered by reverse-hybridization and DNA sequencing. Haematologica. 2002;87(10):1113-14.
87. Jalali H, Mahdavi MR, Roshan P, et al. Alpha thalassemia gene mutations in neonates from Mazandaran, Iran, 2012. Hematology. 2014; 19(4):192-5.
88. Hadavi V, Taromchi AH, Malekpour M, et al. Elucidating the spectrum of α-thalassemia mutations in Iran. haematologica. 2007; 92(7):992-3.
89. Harteveld CL, Yavarian M, Zorai A, et al. Molecular spectrum of α‐thalassemia in the Iranian population of Hormozgan: Three novel point mutation defects. Am J Hematol. 2003; 74(2):99-103.
90. Najmabadi H, Ghamari A, Sahebjam F, et al. Fourteen-year experience of prenatal diagnosis of thalassemia in Iran. Community Genet. 2006; 9(2):93-7.
91. Rachmilewitz EA, Giardina PJ. How I treat thalassemia. Blood. 2011; 118(13):3479-88.
92. Neyshabouri M, Abbasi-Moheb L, Kahrizi K, et al. Alpha-thalassemia: deletion analysis in Iran. Arch Iran Med. 2001; 4(4):160-164
93. Saleh-Gohari N, Khosravi-Mashizi A. Spectrum of α-globin gene mutations in the Kerman Province of Iran. Hemoglobin. 2010; 34(5):451-60.
94. Karamzade A, Mirzapour H, Hoseinzade M, et al. α-globin gene mutations in Isfahan province, Iran. Hemoglobin. 2014; 38(3):161-4.
95. Eftekhari H, Tamaddoni A, Mahmoudi Nesheli H, et al. A comprehensive molecular investigation of α-thalassemia in an Iranian cohort from different provinces of North Iran. Hemoglobin. 2017;41(1):32-37.
96. Dehbozorgian J, Moghadam M, Daryanoush S, et al. Distribution of alpha-thalassemia mutations in Iranian population. Hematology. 2015;20(6):359-62.
97. Khosravi A, Jalali-Far M, Saki N, et al. Evaluation of α-globin gene mutations among different ethnic groups in Khuzestan Province, Southwest Iran. Hemoglobin. 2016;40(2):113-7.
98. Alibakhshi R, Mehrabi M, Omidniakan L, et al. The spectrum of α-thalassemia mutations in Kermanshah Province, West Iran. Hemoglobin. 2015; 39(6):403-6.
99. Garshasbi M, Oberkanins C, Law HY, et al. alpha-globin gene deletion and point mutation analysis among in Iranian patients with microcytic hypochromic anemia. Haematologica. 2003; 88(10):1196-7.
100. Ebrahimkhani S, Azarkeivan A, Bayat N, et al. Genotype-phenotype correlation in Iranian patients with Hb H disease. Hemoglobin. 2011; 35(1):40-6.
101. Farashi S, Najmabadi H. Diagnostic pitfalls of less well recognized HbH disease. Blood Cells Mol Dis. 2015; 55(4):387-95.
102. Akhavan-Niaki H,Youssefi Kamangari R, Banihashemi A, et al. Hematologic features of alpha thalassemia carriers. Int J Mol Cell Med. 2012; 1(3):162-7.
103. Miri-Moghaddam E, Nikravesh A, Gasemzadeh N, et al. Spectrum of alpha-globin gene mutations among premarital Baluch couples in southeastern Iran. Int J Hematol Oncol Stem Cell Res. 2015; 9(3):138-142.
104. Laosombat V, Viprakasit V, Chotsampancharoen T, et al. Clinical features and molecular analysis in Thai patients with HbH disease. Ann Hematol. 2009; 88(12):1185-92.
105. Bayat N, Farashi S, Hafezi-Nejad N, et al. Novel mutations responsible for α-thalassemia in Iranian families. Hemoglobin. 2013;37(2):148-59.
106. Kasraian L, Karimi MH. Hemoglobin. 2015;39(The incidence rate of acute transfusion reactions in thalassemia patients referred to the Shiraz Thalassemia Centre, Shiraz, Iran, before and after the establishment of the hemovigilance system. 4):274-80.
107. Jain A, Kaur R. Hemovigilance and blood safety. Asian J Transfus Sci. 2012; 6(2):137-138.
108. Hervé P, des Floris MFL, Rebibo M, et al. Hemovigilance in France. Rev Bras Hematol Hemoter. 2000; 22(3):368-73.
How to Cite
Nasiri A, Rahimi Z, Vaisi-Raygani A. Hemoglobinopathies in Iran: An Updated Review. Int J Hematol Oncol Stem Cell Res. 14(2):140-150.
Review Article(s)