Genetic heterogeneity of thalassemia major patients in Rembang Regency, Central Java, Indonesia

Nyoman Suci Widyastiti; Ita Margaretha Nainggolan; Edward Kurnia Setiawan Limijadi; Meita Hendrianingtyas; Dwi Retnoningrum; Ariosta; Yetty Movieta Nency; Mayasari Dewi; Sutamti; Tri Ratnaningsih; Usi Sukorini

doi:10.15562/bmj.v12i2.4482

Genetic heterogeneity of thalassemia major patients in Rembang Regency, Central Java, Indonesia

Nyoman Suci Widyastiti ,

Ita Margaretha Nainggolan ,

Edward Kurnia Setiawan Limijadi ,

Meita Hendrianingtyas ,

Dwi Retnoningrum ,

Ariosta ,

Yetty Movieta Nency ,

Mayasari Dewi ,

Sutamti ,

Tri Ratnaningsih ,

Usi Sukorini ,

pdf |
DOI: https://doi.org/10.15562/bmj.v12i2.4482 |
Published: 2023-05-18

Abstract

Link of Video Abstract: https://www.youtube.com/watch?v=RG95aJkUndg

Background: Thalassemia and hemoglobinopathies are caused by mutations in the globin genes that reduce haemoglobin synthesis. In many Asian countries, including Indonesia, thalassemia is a common inherited disorder. Thalassemia has specific characteristics due to the wide variability of the mutations from various populations. Therefore, screening protocol should be designed on specific populations’ regional gene mutation patterns. This study aims to investigate the mutational diversity of the globin genes in thalassemia major patients in Rembang Regency, Central Java, Indonesia.

Methods: Genetic mutations were carried out in all major thalassemia patients who were recorded and underwent routine blood transfusions at the Rembang District Hospital from 2018 – 2020. Mutation identification was carried out using a PCR- RFLP (Polymerase Chain Reaction-Restriction Fragment Length Polymorphism) based method, the ACRS (Amplified Created Restriction Site) method, and genome sequencing.

Results: The most common genotypes are double heterozygous HbE and Cd 35 mutation (-C) (42.87%), HbE and IVS1-nt.5 mutations (G> C) (28.57%), HbE and IVS1- nt.2 mutations (T> C), HbE and codon 8/9 (insertion + G), codon 8/9 (insertion + G) and Hb Malay, as well as Hb Adana and Hb Constant Spring (1.74%).

Conclusion: The β-thalassemia and α-thalassemia mutations most commonly found in Rembang Regency are Cd 35 (-C) and non-deletional mutations.

References

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Al-Mosawy, Wafaa. The Beta-Thalassemia. Sci J Med Res. 2017;1(1):24-30.
Birgens H, Ljung R. The thalassaemia syndromes. Scand J Clin Lab Invest. 2007;67(1):11-25.
Li CK. New trend in the epidemiology of thalassaemia. Best Practice Research Clinical Obstetry Gynaecology. 2017;39:16-26.
Bureau of Communication and Community Services, Ministry of Health of the Republic of Indonesia. Important Screening to Prevent Thalassemia. 2017 [Cited at May 7th 2023]. [Available on: http://www.depkes.go.id/article/view/17050900002/skrining-penting-untuk-cegah-talasemia.html]
Betts M, Flight PA, Paramore C, Tian L, Milenkovic D, Sheth S. Systematic Literature Review of the Burden of Disease and Treatment for Transfusion-dependent β-thalassemia. Clinical Therapeutics 2020;42(2):322-337.
Turner M, Deshpande S, Chitnis M, Byrnes M, Pelligra C, MacEachen AR, et al. A Global Systematic Literature Review on the Burden of Illness in Transfusion-Dependent β-Talasemia. Blood 2019;134(Suppl 1):5786.
Directorate of Prevention and Control of Non-Communicable Diseases, Ministry of Health of the Republic of Indonesia. Thalassemia, The 5th High Cost Disease in Indonesia. 2019 [Cited at May 7th 2023]. [Available at http://www.p2ptm.kemkes.go.id/kegiatan-p2ptm/pusat-/talasemia-penyakit-berbiaya-tinggi-ke-5-di-indonesia].
Fucharoen S, Winichagoon P. Haemoglobinopathies in southeast Asia. Indian J Med Res. 2011;134(4):498-506.
Rujito L, Basalamah M, Mulatsih S, Sofro AS. Molecular Scanning of β-Talasemia in the Southern Region of Central Java, Indonesia; a Step Towards a Local Prevention Program. Hemoglobin. 2015; 39(5): 330-333.
Maskoen AM, Rahayu NS, Reniarti L, Susanah S, Laksono B, Fauziah PN, et al. Mutation spectrum of β-globin gene in thalassemia patients at Hasan Sadikin Hospital - West Java Indonesia. Cellular and Molecular Biology. 2017;63(12):22-24.
Hernanda PY, Tursilowati L, Arkesteijn SGJ, Ugrasena IDG, Larasati MCS, Soeatmadji SM, et al. Towards a Prevention Program for β-Thalassemia. The Molecular Spectrum in East Java, Indonesia. Hemoglobin. 2012;36(1):1-6.
Elmia, Nasrul E, Syukur S, Susanah S. Molecular Detection of Beta-Globin Gene Mutations of Ethnic Riau Malay Thalassaemia Patients by Polymerase Chain Reaction and Sequens DNA. American Scientific Research Journal for Engineering, Technology, and Sciences. 2017;38(2):18-22.
Adhiyanto C, Susianti Y, Rahmawati NM, Badriah F, Harriati Z, Raisha R. Screening of ß-Globin Gene Mutations in Adolescent Schoolgirls in Rural Malang and Sukabumi City, Java Province, Indonesia. Proceedings of the 1st International Integrative Conference on Health, Life and Social Sciences (ICHLaS 2017). Atlantis Press. 2017 [Cited at May 7th 2023]. [Available on: https://www.atlantis-press.com/proceedings/ichlas-17/25887030].
Susanto ZA, Siswandari W, Rujito L. Cd60 (GTG > GAG)/Hb Cagliari mutation was found in scanning of ß thalassemia alleles from patients of East Kalimantan, Indonesia. Molecular Genetics and Metabolism Reports. 2020;22:100550.
Wahidiyat PA, Gatot D, Tjitrasari T, Ringoringo HP, Marzuki NS, Taufani RA, et al. Phenotypic diversity in beta‐HbE talasemia patients. Paediatrica Indonesiana. 2006;46(2):82-86.
Nainggolan IM, Harahap A, Ambarwati DD. Interaction Of Haemoglobin Adana (Haemoglobin A : c.179G>A) With Deletional And Nondeletional a(+)-Thalassemia Mutations: Diverse Hematological And Clinical Features. Hemoglobin. 2013;37(3):297-305.
Nainggolan IM, Harahap A, Setianingsih I. Hydrops Fetalis Associated with Homozygosity for Hb Adana [α59(E8)Gly→Asp (α2)]. Hemoglobin. 2010;34(4):394-401.
Pramoonjago P, Harahap A, Taufani RA, Setianingsih I, Marzuki S, Harahap A. Rapid screening for the most common beta thalassaemia mutations in south east Asia by PCR based restriction fragment length polymorphism analysis (PCR-RFLP). J Med Genet. 1999;36(12):937-938.
Hassan S, Ahmad R, Zakaria Z, Zulkafli Z, Abdullah WZ. Detection of β-globin Gene Mutations Among β-thalassaemia Carriers and Patients in Malaysia: Application of Multiplex Amplification Refractory Mutation System-Polymerase Chain Reaction. Malays J Med Sci. 2013;20(1):13-20.
George E. HbE β-Thalassaemia in Malaysia: Revisited. Journal of Hematology & Thromboembolic Diseases. 2013;1(1):1-3.
Azma RZ, M-Gaus K, A-Aziz S, Alauddin H, Ithnin A, Razak NF, et al. Detection of Homozygous Haemoglobin Constant Spring by Capillary Electrophoresis Method. ARC Journal of Hematology. 2016;1(1):28–32.
Muktiarti D, Wahidiyat PA, Nainggolan IM, Setianingsih I. Talasemia Alfa Mayor dengan Mutasi Non-Delesi Heterozigot Ganda. Sari Pediatri. 2006;8(3):244-250.
Widyastiti NS, Kurnia EL, Retnoningrum D, Nainggolan IM. Compound heterozygous alpha-thalassemia 3.7 kb deletion and hemoglobin adana: a case report. Bali Medical Journal. 2021;10(3):1129-1132.
Widyastiti NS, Nainggolan IM, Kurnia EL, Retnoningrum D, Budiwiyono I. A rare case of Hb H disease caused by compound heterozygous for α talasemia and Hb Quong Sze in Chinese Indonesian proband: A case report. Bali Medical Journal. 2013;8(2):333-336.
Alauddin H, Noor-Adilah Jaapar, Raja Z. Azma, Azlin Ithnin, Noor-Farisah A. Razak, C-Khai Loh, Hamidah Alias, Zarina Abdul-Latiff, and Ainoon Othman. A Case Series of a-Thalassemia Intermedia Due to Compound Heterozygosity for Hb Adana [HBA2: c179G4A (or HBA1); p.Gly60Asp] With Other a-Thalassemias in Malay Families. Hemoglobin. 2014; 38(4):277–281.
Harahap RIM, Prihatni D, Rostini T. The compatibility measurement of Mentzer, England & Fraser, Shine & Lal, and Srivastava indices to the hemoglobin electrophoresis result for beta thalassemia trait screening. Bali Medical Journal. 2019;8(2):311-315.

[1] Galanello R., Origa R. Beta-thalassemia. Orphanet J Rare Dis. 2010;5:11.

[2] Al-Mosawy, Wafaa. The Beta-Thalassemia. Sci J Med Res. 2017;1(1):24-30.

[3] Birgens H, Ljung R. The thalassaemia syndromes. Scand J Clin Lab Invest. 2007;67(1):11-25.

[4] Li CK. New trend in the epidemiology of thalassaemia. Best Practice Research Clinical Obstetry Gynaecology. 2017;39:16-26.

[5] Bureau of Communication and Community Services, Ministry of Health of the Republic of Indonesia. Important Screening to Prevent Thalassemia. 2017 [Cited at May 7th 2023]. [Available on: http://www.depkes.go.id/article/view/17050900002/skrining-penting-untuk-cegah-talasemia.html]

[6] Betts M, Flight PA, Paramore C, Tian L, Milenkovic D, Sheth S. Systematic Literature Review of the Burden of Disease and Treatment for Transfusion-dependent β-thalassemia. Clinical Therapeutics 2020;42(2):322-337.

[7] Turner M, Deshpande S, Chitnis M, Byrnes M, Pelligra C, MacEachen AR, et al. A Global Systematic Literature Review on the Burden of Illness in Transfusion-Dependent β-Talasemia. Blood 2019;134(Suppl 1):5786.

[8] Directorate of Prevention and Control of Non-Communicable Diseases, Ministry of Health of the Republic of Indonesia. Thalassemia, The 5th High Cost Disease in Indonesia. 2019 [Cited at May 7th 2023]. [Available at http://www.p2ptm.kemkes.go.id/kegiatan-p2ptm/pusat-/talasemia-penyakit-berbiaya-tinggi-ke-5-di-indonesia].

[9] Fucharoen S, Winichagoon P. Haemoglobinopathies in southeast Asia. Indian J Med Res. 2011;134(4):498-506.

[10] Rujito L, Basalamah M, Mulatsih S, Sofro AS. Molecular Scanning of β-Talasemia in the Southern Region of Central Java, Indonesia; a Step Towards a Local Prevention Program. Hemoglobin. 2015; 39(5): 330-333.

[11] Maskoen AM, Rahayu NS, Reniarti L, Susanah S, Laksono B, Fauziah PN, et al. Mutation spectrum of β-globin gene in thalassemia patients at Hasan Sadikin Hospital - West Java Indonesia. Cellular and Molecular Biology. 2017;63(12):22-24.

[12] Hernanda PY, Tursilowati L, Arkesteijn SGJ, Ugrasena IDG, Larasati MCS, Soeatmadji SM, et al. Towards a Prevention Program for β-Thalassemia. The Molecular Spectrum in East Java, Indonesia. Hemoglobin. 2012;36(1):1-6.

[13] Elmia, Nasrul E, Syukur S, Susanah S. Molecular Detection of Beta-Globin Gene Mutations of Ethnic Riau Malay Thalassaemia Patients by Polymerase Chain Reaction and Sequens DNA. American Scientific Research Journal for Engineering, Technology, and Sciences. 2017;38(2):18-22.

[14] Adhiyanto C, Susianti Y, Rahmawati NM, Badriah F, Harriati Z, Raisha R. Screening of ß-Globin Gene Mutations in Adolescent Schoolgirls in Rural Malang and Sukabumi City, Java Province, Indonesia. Proceedings of the 1st International Integrative Conference on Health, Life and Social Sciences (ICHLaS 2017). Atlantis Press. 2017 [Cited at May 7th 2023]. [Available on: https://www.atlantis-press.com/proceedings/ichlas-17/25887030].

[15] Susanto ZA, Siswandari W, Rujito L. Cd60 (GTG > GAG)/Hb Cagliari mutation was found in scanning of ß thalassemia alleles from patients of East Kalimantan, Indonesia. Molecular Genetics and Metabolism Reports. 2020;22:100550.

[16] Wahidiyat PA, Gatot D, Tjitrasari T, Ringoringo HP, Marzuki NS, Taufani RA, et al. Phenotypic diversity in beta‐HbE talasemia patients. Paediatrica Indonesiana. 2006;46(2):82-86.

[17] Nainggolan IM, Harahap A, Ambarwati DD. Interaction Of Haemoglobin Adana (Haemoglobin A : c.179G>A) With Deletional And Nondeletional a(+)-Thalassemia Mutations: Diverse Hematological And Clinical Features. Hemoglobin. 2013;37(3):297-305.

[18] Nainggolan IM, Harahap A, Setianingsih I. Hydrops Fetalis Associated with Homozygosity for Hb Adana [α59(E8)Gly→Asp (α2)]. Hemoglobin. 2010;34(4):394-401.

[19] Pramoonjago P, Harahap A, Taufani RA, Setianingsih I, Marzuki S, Harahap A. Rapid screening for the most common beta thalassaemia mutations in south east Asia by PCR based restriction fragment length polymorphism analysis (PCR-RFLP). J Med Genet. 1999;36(12):937-938.

[20] Hassan S, Ahmad R, Zakaria Z, Zulkafli Z, Abdullah WZ. Detection of β-globin Gene Mutations Among β-thalassaemia Carriers and Patients in Malaysia: Application of Multiplex Amplification Refractory Mutation System-Polymerase Chain Reaction. Malays J Med Sci. 2013;20(1):13-20.

[21] George E. HbE β-Thalassaemia in Malaysia: Revisited. Journal of Hematology & Thromboembolic Diseases. 2013;1(1):1-3.

[22] Azma RZ, M-Gaus K, A-Aziz S, Alauddin H, Ithnin A, Razak NF, et al. Detection of Homozygous Haemoglobin Constant Spring by Capillary Electrophoresis Method. ARC Journal of Hematology. 2016;1(1):28–32.

[23] Muktiarti D, Wahidiyat PA, Nainggolan IM, Setianingsih I. Talasemia Alfa Mayor dengan Mutasi Non-Delesi Heterozigot Ganda. Sari Pediatri. 2006;8(3):244-250.

[24] Widyastiti NS, Kurnia EL, Retnoningrum D, Nainggolan IM. Compound heterozygous alpha-thalassemia 3.7 kb deletion and hemoglobin adana: a case report. Bali Medical Journal. 2021;10(3):1129-1132.

[25] Widyastiti NS, Nainggolan IM, Kurnia EL, Retnoningrum D, Budiwiyono I. A rare case of Hb H disease caused by compound heterozygous for α talasemia and Hb Quong Sze in Chinese Indonesian proband: A case report. Bali Medical Journal. 2013;8(2):333-336.

[26] Alauddin H, Noor-Adilah Jaapar, Raja Z. Azma, Azlin Ithnin, Noor-Farisah A. Razak, C-Khai Loh, Hamidah Alias, Zarina Abdul-Latiff, and Ainoon Othman. A Case Series of a-Thalassemia Intermedia Due to Compound Heterozygosity for Hb Adana [HBA2: c179G4A (or HBA1); p.Gly60Asp] With Other a-Thalassemias in Malay Families. Hemoglobin. 2014; 38(4):277–281.

[27] Harahap RIM, Prihatni D, Rostini T. The compatibility measurement of Mentzer, England & Fraser, Shine & Lal, and Srivastava indices to the hemoglobin electrophoresis result for beta thalassemia trait screening. Bali Medical Journal. 2019;8(2):311-315.

Genetic heterogeneity of thalassemia major patients in Rembang Regency, Central Java, Indonesia

Abstract

References

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