The Haematological and Molecular Characteristics of Hb Singapore [HBA2: c.425G>C] Unique Among the Malays from Kelantan, Malaysia
Keywords:
Hb J, thalassaemia, alpha variant, molecular analysis, unique variant among MalaysAbstract
Background: Haemoglobin (Hb) Singapore is a rare alpha variant that typically involved alpha-2 gene. Misidentification can occur without molecular diagnosis as the characteristics in Hb analysis is typical of Hb J variant. Objective: This study aims to describe the haematological parameters, phenotype and genotype characterisation of Hb Singapore along with a proposed classification of the variant based on American Collage of Molecular Genetics and Genomics (ACMG) guideline. Methods: Analysis involved nineteen confirmed cases of Hb Singapore retrieved from our databases. Cases referred to Institute for Medical Research (IMR) from 2018 to 2022. The clinical information and haematological parameters provided by the hospitals were evaluated. The cases were subjected to direct sequencing of HBA gene for variant detection. Results: Interestingly, all recorded cases involved Malay patients, predominantly from Kelantan (n=16, 80%). There were (n=7, 36.8%) males and (n=12, 63.2%) females. The median age of the cases was 26 years old with age ranges between 2 to 56 years old. All individuals were asymptomatic during the screening with most of them being screened as part of the National Thalassaemia Screening Programme and (n=3,15.8%) were suspected of Hb variant after an abnormal HbA1c finding as part of routine monitoring for diabetes mellitus follow-up. All of them had haematological features of thalassaemia trait with the mean + SD for Hb, MCV and MCH were 14.9g/dl + 2.0, 81.1 ± 7.7 fL and 26.5 ± 3.2 pg respectively. Three genotypes were identified; ααHb Singapore/αα (n=17, 89.5%), ααHb Singapore/αα, βCD 26/β (n=1, 5.3%), ααHb Singapore/αα, Gγ(Aγδβ)º-thal, Asian-Indian inversion/deletion (n=1, 5.3%). Conclusion: Interestingly, two cases were associated with two different mutations which are co-inherited with HbE and Gγ(Aγδβ)º-thal, Asian-Indian inversion/deletion without apparent effect on the variant expression. This is the largest reported case of Hb Singapore in the literature and the unique ethnicity affected by this variant suggested that it is higher among Malays from Kelantan. Based on our data, we propose to classify this variant as a benign or likely benign variant (B/LB).
Downloads
References
Ahmad, R. et al. (2012) ‘Distribution of alpha thalassaemia in 16 year old Malaysian students in Penang, Melaka and Sabah’, Medical Journal of Malaysia, 67(6), pp. 565–570.
Ahmad, R. et al. (2013) ‘Distribution of alpha thalassaemia gene variants in diverse ethnic populations in Malaysia: Data from the institute for medical Research’, International Journal of Molecular Sciences, 14(9), pp. 18599–18614. doi: 10.3390/ijms140918599.
Alwi, Z. Bin and Syed-Hassan, S. N. R. K. (2022) ‘Thalassemia in Malaysia’, Hemoglobin, 46(1), pp. 45–52. doi: 10.1080/03630269.2022.2057326.
Angastiniotis M, Eleftheriou A, Galanello R, Harteveld CL, Petrou M, Traeger-Synodinos J, Giordano P, Jauniaux E, Modell B, S. G. (2013) ‘Prevention of Thalassaemias and Other Haemoglobin Disorders: Volume 1: Principles [Internet]. Old J, editor. 2nd ed. Nicosia (Cyprus): Thalassaemia International Federation’.
Arnold S.-C. Tan, Thuan C. Quah, Poh S. Low, and S. S. C. (2001) ‘A rapid and reliable 7-deletion multiplex polymerase chain reaction assay for a-thalassemia’, Blood, 98(1), pp. 250–251.
Clegg, J. B. et al. (1969) ‘Two new haemoglobin variants involving proline substitutions’, Nature, 222(5191), pp. 379–380. doi: 10.1038/222379a0.
Elizabeth, G. and Ann, M. T. J. A. (2010) ‘Genotype-phenotype diversity of beta-thalassemia in Malaysia: Treatment options and emerging therapies’, Medical Journal of Malaysia, 65(4), pp. 256–260.
George, E. (2013) 'HbE β-Thalassaemia in Malaysia : Revisited’, Journal of Haematology and Thromboembolic Diseases, pp. 1–3. doi: 10.4172/2329-8790.
Giardine, B. et al. (2014) ‘Updates of the HbVar database of human hemoglobin variants and thalassemia mutations’, Nucleic Acids Research, 42(D1), pp. 1063–1069. doi: 10.1093/nar/gkt911.
Greene, D. N. et al. (2012) ‘Clinica Chimica Acta Comparison of Sebia Capillarys Flex capillary electrophoresis with the BioRad Variant II high pressure liquid chromatography in the evaluation of hemoglobinopathies’, Clinica Chimica Acta, 413(15–16), pp. 1232–1238. doi: 10.1016/j.cca.2012.03.027.
Henderson, S. J. et al. (2015) ‘Ten Years of Routine α - and β -Globin Gene Sequencing in UK Hemoglobinopathy Referrals Reveals 60 Novel Mutations Ten Years of Routine a - and b -Globin Gene Sequencing in UK Hemoglobinopathy Referrals Reveals 60 Novel Mutations’, Haemoglobin. doi: 10.3109/03630269.2015.1113990.
Kountouris, P. et al. (2014) ‘IthaGenes: An interactive database for haemoglobin variations and epidemiology’, PLoS ONE, 9(7). doi: 10.1371/journal.pone.0103020.
Kountouris, P. et al. (2022) ‘Adapting the ACMG/AMP variant classification framework: A perspective from the ClinGen Hemoglobinopathy Variant Curation Expert Panel’, Human Mutation, 43(8), pp. 1089–1096. doi: 10.1002/humu.24280.
Mandrile, G. et al. (2022) ‘First and Second Level Haemoglobinopathies Diagnosis: Best Practices of the Italian Society of Thalassemia and Haemoglobinopathies (SITE)’, Journal of Clinical Medicine, 11(18). doi: 10.3390/jcm11185426.
Mohd Ibrahim H, Muda Z, Othman IS, Mohamed Unni MN, Teh KH, Thevarajah A, Gunasagaran K, Ong GB, Yeoh SL, Muhammad Rivai A, Che Mohd Razali CH, Din ND, Abdul Latiff Z, Jamal R, Mohamad N, Mohd Ariffin H, Alias H. Observational study on the current status of thalassaemia in Malaysia: a report from the Malaysian Thalassaemia Registry. BMJ Open. 2020 Jun 29;10(6):e037974. doi: 10.1136/bmjopen-2020-037974. PMID: 32601117; PMCID: PMC7328811.
Mohd Sahid, E. N. M. S., Esa, E. E., Yasin, N. Y., Su Yee, K. S. Y., & Zakaria, Z. (2018). A rare hemoglobin variant, Hb Arya in a Malay woman. Asian Journal of Medicine and Biomedicine. 00, p. 7. Available at: https://journal.unisza.edu.my/ajmb/index.php/ajmb/article/view/148
Oleske, D. A. et al. (2014) ‘Higher Sensitivity of Capillary Electrophoresis in Detecting Hemoglobin A2 ’ compared to traditional gel electrophoresis’, Ann Clin Lab Sci, 44(3), pp. 291–293. PMID: 25117100
Raja Sabudin, R. Z. A. et al. (2014) ‘Molecular characteristic of alpha thalassaemia among patients diagnosed in UKM Medical Centre’, Malaysian Journal of Pathology, 36(1), pp. 27–32. Available at: http://www.mjpath.org.my/2014/v36n1/alpha-thalassaemia.pdf.
Richard T. Jones, B. B. and R. L. (1967) ‘Chemical characterization of Haemoglobin Mexico and Haemoglobin Chiapas’, Biochimica et Biophysica Acta., 154(1968), pp. 488–495.
Shrestha, A. K. et al. (2022) ‘Hemoglobin J in a patient with severe anemia, a case report from Nepal’, Annals of Medicine and Surgery, 82(September), p. 104703. doi: 10.1016/j.amsu.2022.104703.
Srinivas, U., Mahapatra, M. and Pati, H. P. (2007) ‘Hb J Meerut, a fast-moving hemoglobin - A study of seven cases from India and a review of literature’, American Journal of Hematology, 82(7), pp. 666–667. doi: 10.1002/ajh.20826.
Thom, C. S. et al. (2013) ‘Hemoglobin variants: Biochemical properties and clinical correlates’, Cold Spring Harbor Perspectives in Medicine, 3(3). doi: 10.1101/cshperspect.a011858.
Yap, S.-F. et al. (2005) ‘Heterogeneity in alpha-thalassemia interactions in Malays, Chinese and Indians in Malaysia’, Journal of Obstetrics and Gynaecology Research, 31(6), pp. 540–546. doi: 10.1111/j.1447-0756.2005.00333.x.
Downloads
Published
Issue
Section
License
Copyright (c) 2024 Malaysian Journal of Human Genetics
This work is licensed under a Creative Commons Attribution 4.0 International License.
