Molecular Heterogeneity of Hb H Disease in India
Abstract
:1. Introduction
2. Materials and Methods
3. Results
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Weatherall, D.J.; Clegg, J.B. Inherited hemoglobin disorders: An increasing global health problem. Bull. World Health Org. 2001, 79, 704–712. [Google Scholar] [PubMed]
- Desai, S.N.; Colah, R.B. Alpha-thalassemia syndromes in India. Indian J. Hum. Genet. 1997, 3, 1–9. [Google Scholar]
- Higgs, D.R.; Weatherall, D.J. The α Thalassemias. Cell. Mol. Life Sci. 2009, 66, 1154–1162. [Google Scholar] [CrossRef] [PubMed]
- Chui, D.H.; Fucharoen, S.; Chan, V. Hemoglobin H disease: Not necessarily a benign disorder. Blood 2003, 101, 791–800. [Google Scholar] [CrossRef] [Green Version]
- Chen, F.E.; Ooi, C.; Ha, S.Y.; Cheung, B.M.; Todd, D.; Liang, R.; Chan, T.K.; Chan, V. Genetic and clinical features of hemoglobin H disease in Chinese patients. N. Engl. J. Med. 2000, 343, 544–550. [Google Scholar] [CrossRef] [Green Version]
- Chui, D.H. Alpha thalassemia: Hb H disease and Hb Bart’s hydrops fetalis. Ann. N. Y. Acad. Sci. 2005, 1054, 25–32. [Google Scholar] [CrossRef]
- Kanavakis, E.; Papassotiriou, I.; Karagiorga, M.; Vrettou, C.; Metaxotou Mavrommati, A.; Stamoulakatou, A.; Kattamis, C.; Traeger-Synodinos, J. Phenotypic and molecular diversity of haemoglobin H disease: A Greek experience. Br. J. Haematol. 2000, 111, 915–923. [Google Scholar] [CrossRef]
- Nadkarni, A.; Gorakshakar, A.; Mohanty, D.; Colah, R.B. Alpha genotyping in a heterogeneous Indian population. Am. J. Hematol. 1996, 53, 149–150. [Google Scholar] [CrossRef]
- Lal, A.; Goldrich, M.L.; Haines, D.A.; Azimi, M.; Singer, S.T.; Vichinsky, E.P. Heterogeneity of Hemoglobin H disease in childhood. N. Engl. J. Med. 2011, 364, 710–718. [Google Scholar] [CrossRef] [Green Version]
- Wajcman, H.; Traeger-Synodinos, J.; Papassotiriou, I.; Giordano, P.; Hartweld, C.; Baudin-Creuza, V.; Old, J. Unstable and thalassemic alpha chain hemoglobin variants: A cause of Hb H disease and thalassemia intermedia. Hemoglobin 2008, 32, 327–349. [Google Scholar] [CrossRef]
- Nair, S.; Nadkarni, A.; Ghosh, K.; Colah, R. Variable presentation of Hb H Disease due to homozygosity for the rare polyadenylation signal A T (Indian) (AATAAA >AATA– –) mutation in four Indian families. Hemoglobin 2013, 37, 277–284. [Google Scholar] [CrossRef] [PubMed]
- Moher, D.; Shamseer, L.; Clarke, M.; Ghersi, D.; Liberati, A.; Petticrew, M.; Shekelle, P.; Stewart, L. PRISMA-p group. Preferred reporting items for systematic reviewand meta-analysis protocols (PRISMA-P) 2015 statement. Syst. Rev. 2015, 4, 1. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sarkar, A.; Banerjee, S.; Chandra, S.; Ghosh, M.; Banerjee, D.; Choudhury, M.; Das, M.; Dasgupta, U. A novel 33.3 kb deletion (- -KOL) in the alpha-globin gene cluster: A brief report on deletional alpha-thalassaemia in the heterogeneous eastern Indian population. Br. J. Haematol. 2005, 130, 454–457. [Google Scholar] [CrossRef] [PubMed]
- Nadkarni, A.; Nair, S.; Italia, K.; Warang, P.; Dalvi, M.; Ghosh, K.; Colah, R. Molecular diversity of Hemoglobin H disease in India. Am. J. Clin. Pathol. 2010, 133, 491–494. [Google Scholar] [CrossRef] [PubMed]
- Das, R.; Fisher, C.; Hira, J.; Helena, A.; Tehran, A.; Bansal, D.; Sharma, P.; Malhotra, P.; Higgs, D.; Weatherall, D. Wide spectrum of molecular and clinical heterogeneity in HbH disease in North Indian patients. Blood 2014, 124, 1325. [Google Scholar] [CrossRef]
- Sharma, P.; Das, R.; Khadwal, A.; Karmakar, I.; Hira, J.; Chhabra, S. HbH disease due to compound heterozygosity for hemoglobins Zürich-Albisrieden and Sallanches. Pediatr. Blood Cancer 2020, 67, e28161. [Google Scholar] [CrossRef]
- Hall, G.W.; Higgs, D.R.; Murphy, P.; Villegas, A.; de Miguel, A. A mutation in the polyadenylation signal of the alpha 2 globin gene (AATAAA → AATA--) as a cause of alpha thalassaemia in Asian Indians. Br. J. Haematol. 1994, 88, 225–227. [Google Scholar] [CrossRef]
- Shaji, R.; Eunice, S.; Baidya, S.; Srivastava, A.; Chandy, M. Determination of the breakpoint and molecular diagnosis of a common alpha-thalassaemia-1 deletion in the Indian population. Br. J. Haematol. 2003, 123, 942–947. [Google Scholar] [CrossRef] [Green Version]
- Warang, P.; Nair, S.; Nadkarni, A.; Ghosh, K.; Colah, R.B. Hb H disease due to homozygosity for a rare alpha 2-globin variant, Hb Sallanches. Hemoglobin 2010, 34, 45–48. [Google Scholar] [CrossRef]
- Nadkarni, A.; Gorakshakar, A.; Sawant, P.; Italia, K.; Upadhye, D.; Gorivale, M.; Mehta, P.; Hariharan, P.; Ghosh, K.; Colah, R. The phenotypic and molecular diversity of hemoglobinopathies in India: A review of 15 years at a referral center. Int. J. Lab. Hematol. 2019, 41, 218–226. [Google Scholar] [CrossRef]
- Dash, S.; Harano, K.; Menon, S. Hb Sallanches {alpha 104 (G11) cys>tyr, TGC>TAC (Alpha 2)}; An unstable hemoglobin variant found in an Indian child. Hemoglobin 2006, 30, 393–396. [Google Scholar] [CrossRef] [PubMed]
- Deshpande, P.; Kamalanathan, N.; Sampath, E.; George, B.; Shaji, R.V.; Edison, E.S. Characterization of clinical and laboratory profiles of the deletional α2-globin gene polyadenylation signal sequence (AATAAA > AATA- -) in an Indian population. Hemoglobin 2015, 39, 415–418. [Google Scholar] [CrossRef] [PubMed]
- Roy, P.; Bhattacharya, G.; Banerjee, D.; Chandra, S.; Ghosh, M.; Choudhuri, U.; Das, M.; Dasgupta, U.B. Hb Sallanches [alpha104(G11)Cys → Tyr, TGC>TAC] occurs frequently on the Indian subcontinent. Hemoglobin 2009, 33, 486–491. [Google Scholar] [CrossRef] [PubMed]
- Fei, Y.J.; Liu, J.C.; Jogessar, V.B.; Westermeyer, K.R.; Bridgemohan, R.; Huisman, T.H. Combinations of three different forms of alpha-thalassemia in a large Indian family from Durban, South Africa: Hematological observations. Acta. Haematol. 1992, 87, 11–15. [Google Scholar] [CrossRef]
- Moore, J.A.; Pullon, B.M.; Drake, K.M.; Brennan, S.O. Novel α0-thalassemia deletion identified in an Indian infant with Hb H disease. Hemoglobin 2020, 44, 297–301. [Google Scholar] [CrossRef]
- Fucharoen, S.; Viprakasit, V. Hb H disease: Clinical course and disease modifiers. Hematol. Am. Soc. Hematol. Educ. Program. 2009, 2009, 6–34. [Google Scholar] [CrossRef] [Green Version]
- Vandenplas, S.; Higgs, D.R.; Nicholls, R.D.; Bester, A.J.; Mathew, C. Characterization of a new alpha zero thalassaemia defect in the South African population. Br. J. Haematol. 1987, 66, 539–542. [Google Scholar] [CrossRef]
- Drysdale, H.C.; Higgs, D.R. Alpha-thalassaemia in an Asian Indian. Br. J. Haematol. 1988, 68, 264. [Google Scholar] [CrossRef]
- Bhattacharya, G.; Sarkar, A.; Benerjee, D.; Chandra, S.; Das, M.; Dasgupta, U. Polymerase chain reaction-based search for two α-globin gene mutations in India. Hemoglobin 2008, 32, 485–490. [Google Scholar] [CrossRef]
- Morlé, F.; Francina, A.; Ducrocq, R.; Wajcman, H.; Gonnet, C.; Philippe, N.; Souillet, G.; Godet, J. A new α chain variant Hb Sallanches [α2 104(G11)Cys → Tyr] associated with Hb H disease in one homozygous patient. Br. J. Haematol. 1995, 91, 608–611. [Google Scholar] [CrossRef]
- Fucharoen, S.; Winichagoon, P. Thalassemia in Southeast Asia: Problem and strategy for prevention and control. J. Trop. Med. 1992, 23, 647–655. [Google Scholar]
- Merritt, D.; Jones, R.T.; Head, C.; Thibodeau, S.N.; Fairbanks, V.F.; Steinberg, M.H.; Coleman, M.B.; Rodgers, G.P. Hb Seal Rock [(alpha 2)142 term → Glu, codon 142 TAA → GAA]: An extended alpha chain variant associated with anemia, microcytosis, and alpha-thalassemia-2 (−3.7 Kb). Hemoglobin 1997, 21, 331–344. [Google Scholar] [CrossRef] [PubMed]
Sr.No. | Mutation (HGVS Nomenclature) | HbH Genotype | No. of Cases | Clinical Presentation | Ref. |
---|---|---|---|---|---|
1 | α2 Poly A (AATAAA>AATA--) homozygous (HBB:c.*111_*112delAA) | αPoly Aα/αPoly Aα | 4 | Patient 1: H/O anemia and reticulocytosis and no history of receiving any blood transfusions. Patient 2: H/O weakness, easy fatigability and had jaundice twice. Patients 3: H/O severe anemia and mild splenomegaly (spleen 4.5 cms below the costal margin). Patient 4: H/O intermittent fever intermittently, splenomegaly (spleen 9 cms below the costal margin) and regular blood transfusions after 30 days of interval, had underwent splenectomy at the age of 3 years. | [11] |
2 | 3.7 kb (type I) deletion α-2+ 33.3 kb deletion a | -α3.7/--Kol | 1 | Hypochromic microcytic anemia, H/O recurrent jaundice in the past, mild icterus, a a palpable and enlarged liver and spleen, both of which measured 3 cm below the costal margin. | [13] |
3 | 33.3 kb deletion a | αα/--Kol trait | 2 b | Mild and unexplained anemia | |
4 | 3.7 kb (type I) deletion α-2+ α 23601 bp deletion (NG_000006.1:g.34247_38050del + NG_000006.1:g.19464_43064del23601) | -α3.7/--SA | 3 | H/O Microcytic hypochromic anemia with mild splenomegaly, (3 cm below the costal margin), H/O pallor and jaundice. | [14] |
5 | 3.7 kb (type I) deletion α-2+ α 19301 bp deletion (NC_000016.10:g.169818_174075del + | –α3.7/--SEA | 2 | Microcytic hypochromic anemia with splenomegaly (3 cm below the costal margin), H/O pallor and jaundice. | |
6 | 3.7 kb (type I) deletion alpha-2 + α2 CD 104 (G→A) (NC_000016.10:g.169818_174075del+ NC_000016.10:g.169818_174075del+ HBA2:c.314G>A) | –α3.7/–α3.7+ HbSallanches | 1 | Microcytic hypochromic anemia with splenomegaly (3 cm below the costal margin), H/O pallor and jaundice. | |
7 | α 23601 bp deletion +3.7 kb (type I) deletion α-2 + α2 CD 104 (G→A) (NG_000006.1:g.19464_43064del23601 + NC_000016.10:g.169818_174075del + HBA2:c.314G>A) | – –SA/–α3.7+Hb Sallanches | 2 | Microcytic hypochromic anemia with splenomegaly (3 cm below the costal margin), H/O pallor and jaundice. | |
8 | 3.7 kb (type I) deletion α-2+ α 23601 bp deletion (NG_000006.1:g.34247_38050del + NG_000006.1:g.19464_43064del23601) | -α3.7/--SA | 3 | Moderate anemia with presentation in the third decade | [15] |
9 | α2 CD104 (G→A) homozygous (HBA2:c.314G>A) | αHbSallanchesα/αHb Sallanchesα | 6 | Severe anemia with early presentation | |
10 | α2 Poly A (AATAAA>AATA--) homozygous (HBB:c.*111_*112delAA) | αPoly Aα/αPoly Aα | 3 | Moderate anemia with presentation in the second decade | |
11 | 3.7 kb (type I) deletion α-2 + α2 CD 104 (G→A) (NC_000016.10:g.169818_174075del + HBA2:c.314G>A) | -α3.7/α HbSallanches α | 1 | Moderate anemia. | |
12 | 3.7 kb (type I) deletion α-2+ α2 142 (T→G) (NC_000016.10:g.169818_174075del + HBA2:c.427T>G) | -α3.7/αSeal Rock α | 1 | Identified during family screening in the forth decade with mild anemia | |
13 | 3.7 kb (type I) deletion α-2 + Novel α0 deletion/Large deletion involving α1 and α2 (NC_000016.10:g.169818_174075del + Novel α0 deletion/Large deletion involving α1 and α2) | -α3.7/-- | 15 | Larger deletions showed early presentation with severe anemia and shorter deletions showed mild anemia | |
14 | α2 142 (T→G)+ Large deletion involving α1 and α2 HBA2:c.427T>G + Large deletion involving α1 and α2 | αSeal Rock α/-- | 1 | Severe anemia with early presentation | |
15 | α2 CD 19 (-G) homozygous HBA2:c.60delG | α2 CD 19 (-G) homozygous | 1 | Severe anemia with early presentation | |
16 | α CD 76 (+T) a + CD 104 (G→A) + HBA2:c.314G>A | α76 + Tα/αHbSallanches α | 1 | Moderate anemia with presentation in the third decade | |
17 | α2 Poly A (AATAAA>AATA--) + α2 CD 130 (G→C) HBB:c.*111_*112delAA + HBA2:c.391G>C | αPoly A α/αHb Sun Prairie α | 1 | Moderate anemia with early presentation | |
18 | α2 Poly A (AATAAA>AATA--) + α CD 76 (+T) a HBB:c.*111_*112delAA | αPolyAα/α76 +Tα | 1 | Moderate anemia with early presentation | |
19 | α2 CD 104 (G→A) + CD 59 (G→C) HBA2:c.314G>A + HBA2:c.178G>C | α α/α HbSallanches αZurich- Albisrieden | 1 | H/O recurrent microcytic hypochromic anemia with reticluocytosis, intermittent blood transfusion needs and jaundice, splenomegaly ( 4 cm below the left costal margin). | [16] |
20 | α2 Poly A (AATAAA>AATA--) homozygous or large deletion + α2 Poly A (AATAAA>AATA--) heterozygous (HBB:c.*111_*112delAA) | αPoly Aα/αPoly Aαor --/α Poly Aα→1 | 1 ** | Hypochromic microcytic anemia $ | [17] |
21 | 3.7 kb (type I) deletion α-2+ α 23601 bp deletion (NG_000006.1:g.34247_38050del + NG_000006.1:g.19464_43064del23601) | -α3.7/--SA | 7 | Hypochromic microcytic anemia $ | [18] |
4.2 kb deletion + α 23601 bp deletion (NC_000016.10:g.169818_174075del + NG_000006.1:g.19464_43064del23601) | -α4.2/--SA | 3 | Hypochromic microcytic anemia $ | ||
22 | 3.7 kb (type I) deletion α-2+ α 16401 bp deletion (NC_000016.10:g.169818_174075del + NG_000006.1:g.24664_41064del16401) | -α3.7/--MED | 1 | Hypochromic microcytic anemia $ | |
23 | α2 Poly A (AATAAA>AATA--) homozygous (HBB:c.*111_*112delAA) | αPoly Aα/αPoly Aα | 2 | Hypochromic microcytic anemia $ | |
24 | α IVS 1-1 (G→A) + α 23601 bp deletion HBA2:c.95+1G>A + NG_000006.1:g.19464_43064del23601 | αIVS 1-1 (G>A)α/--SA | 3 | Hypochromic microcytic anemia $ | |
25 | α2 CD104 (G→A) homozygous (HBA2:c.314G>A) | αHb Sallanchesα/αHb Sallanchesα | 1 | H/O recurrent jaundice and hemolytic anemia with reticulocytosis, hepatosplenomegaly (liver 2 cm and spleen 2 cm below the costal margin, respectively). | [19] |
26 | 3.7 kb (type I) deletion α-2+ α 23601 bp deletion (NG_000006.1:g.34247_38050del + NG_000006.1:g.19464_43064del23601) | -α3.7/--SA | 1 | Not mentioned | [20] |
27 | 3.7 kb (type I) deletion α-2+ α 16401 bp deletion (NC_000016.10:g.169818_174075del + NG_000006.1:g.24664_41064del16401) | -α3.7/--MED | 2 | Not mentioned | |
28 | 3.7 kb (type I) deletion α-2+ α 19301 bp deletion (NC_000016.10:g.169818_174075del + NG_000006.1:g.26264_45564del19301) | -α3.7/--SEA | 7 | Not Mentioned | |
29 | α2 Poly A (AATAAA>AATA--) homozygous (HBB:c.*111_*112delAA) | αPoly Aα/αPoly Aα | 4 | Not mentioned | |
30 | 3.7 kb (type I) deletion α-2 + α2 CD 104 (G→A) (NC_000016.10:g.169818_174075del + HBA2:c.314G>A) | -α3.7/α HbSallanches α | 4 | Not mentioned | |
31 | α 23601 bp deletion +3.7 kb (type I) deletion α-2 + α2 CD 104 (G→A) (NG_000006.1:g.19464_43064del23601 + NC_000016.10:g.169818_174075del + HBA2:c.314G>A) | – –SA/–α3.7+Hb Sallanches | 1 | Not mentioned | |
32 | α 23601 bp deletion+ α2 CD 104 (G→A) (NG_000006.1:g.19464_43064del23601 + HBA2:c.314G>A) | – –SA/αHbSallanchesα | 1 | Not mentioned | |
33 | α 19301 bp deletion+ α2 CD 104 (G→A) (NG_000006.1:g.26264_45564del19301 + HBA2:c.314G>A) | – –SEA/αHbSallanchesα | 1 | Not mentioned | |
34 | α2 CD104 (G→A) homozygous (HBA2:c.314G>A) | αHb Sallanchesα/αHb Sallanchesα | 1 | Hypochromic microcytic anemia with reticulocytosis, H/O pallor, jaundice, thalassemic bone changes, an enlarged liver (2.5 cm below the costal margin) and spleen (5 cm below the costal margin). | [21] |
35 | α2 Poly A (AATAAA>AATA--) homozygous (HBB:c.*111_*112delAA) | αPoly Aα/αPoly Aα | 14 | Hypochromic microcytic anemia with splenomegaly with indirect hyperbilirubinemia and elevated Serum LDH | [22] |
36 | α2 Poly A (AATAAA>AATA--)+ α2 CD 130 (G→C) HBB:c.*111_*112delAA + HBA2:c.391G>C | αPoly A α/αHb Sun Prairie α | 1 c | Severe anemia with intermittent blood transfusion | |
37 | α2 Poly A (AATAAA>AATA--) + α2CD 142 (A→C) HBB:c.*111_*112delAA+ HBA2:c.428A>C | αPolyAα/αKoya Dora α | 1 | Hypochromic microcytic anemia with splenomegaly with indirect hyperbilirubinemia and elevated Serum LDH | |
38 | α2 Poly A (AATAAA>AATA--) + α2CD 22 (C→T) HBB:c.*111_*112delAA+ HBA2:c.69C>T | αPolyAα/αCD 22 (C>T) α | 2 | Hypochromic microcytic anemia with splenomegaly with indirect hyperbilirubinemia and elevated Serum LDH | |
39 | α2 Poly A (AATAAA>AATA--) + α2CD 104 (T→C) HBB:c.*111_*112delAA + HBA2:c.313T>C | αPoly A α/αHb Iberia α | 1 | Hypochromic microcytic anemia with splenomegaly with indirect hyperbilirubinemia and elevated Serum LDH | |
40 | α2 CD104 (G→A) homozygous (HBA2:c.314G>A) | αHb Sallanchesα/αHb Sallanchesα | 1 | Hypochromic microcytic anemia and intermittent blood transfusion | [23] |
41 | 3.7 kb (type I) deletion α-2+ α 23601 bp deletion (NG_000006.1:g.34247_38050del + NG_000006.1:g.19464_43064del23601) | -α3.7/--SA | 5 * | Hypochromic microcytic anemia, with intermittent blood transfusion, mild hepatosplenomegaly † | [24] |
42 | 4.2 kb deletion + α 23601 bp deletion (NC_000016.10:g.169818_174075del + NG_000006.1:g.19464_43064del23601) | -α4.2/--SA | 2 * | Hypochromic microcytic anemia $ | |
43 | 3.7 kb (type I) deletion α-2 + Novel α0 deletion/Large deletion involving α1 and α2 (NC_000016.10:g.169818_174075del + Novel α0 deletion/Large deletion involving α1 and α2) | -α3.7/-- | 1 *** | Hypochromic microcytic anemia with pallor | [25] |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Thaker, P.; Mahajan, N.; Mukherjee, M.B.; Colah, R.B. Molecular Heterogeneity of Hb H Disease in India. Thalass. Rep. 2022, 12, 73-84. https://doi.org/10.3390/thalassrep12030012
Thaker P, Mahajan N, Mukherjee MB, Colah RB. Molecular Heterogeneity of Hb H Disease in India. Thalassemia Reports. 2022; 12(3):73-84. https://doi.org/10.3390/thalassrep12030012
Chicago/Turabian StyleThaker, Pallavi, Namrata Mahajan, Malay B. Mukherjee, and Roshan B. Colah. 2022. "Molecular Heterogeneity of Hb H Disease in India" Thalassemia Reports 12, no. 3: 73-84. https://doi.org/10.3390/thalassrep12030012
APA StyleThaker, P., Mahajan, N., Mukherjee, M. B., & Colah, R. B. (2022). Molecular Heterogeneity of Hb H Disease in India. Thalassemia Reports, 12(3), 73-84. https://doi.org/10.3390/thalassrep12030012