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A single centre study on birth of children with transfusion-dependent thalassaemia in Malaysia and reasons for ineffective prevention

Ngim CF, Ibrahim H, Lai NM, Ng CS

Prenat Diagn, 2015 Jan;35(1):51-9.
PMID: 25156332 DOI: 10.1002/pd.4484

We aimed to identify factors contributing to ineffective prevention of thalassaemia in Malaysia by studying events leading to the births of children with transfusion-dependent thalassaemia (TDT) including their parents' reproductive choices.

Matched MeSH terms: Thalassemia/diagnosis*
Fulltext Prevalence of 3.7 and 4.2 deletions in Sudanese patients with red cells hypochromia and microcytosis

Osman HA, Hamid MMA, Ahmad RB, Saleem M, Abdallah SA

BMC Res Notes, 2020 Feb 10;13(1):65.
PMID: 32041645 DOI: 10.1186/s13104-020-4933-5

OBJECTIVE: Alpha-thalassemia is a genetic disorder characterized by deletions of one or more α globin genes that result in deficient of α globin chains reducing haemoglobin concentration. The study aimed to screen 97 patients with microcytosis and hypochromasia for the 3.7 and 4.2 alpha thalassemia deletion mutations.
RESULTS: Out of 97 patients screened, only 7 were carriers for the 3.7 deletion and all patients were negative for the 4.2 deletion. The 3.7 deletion was found in Foor, Hawsa and Rezagat Sudanese tribes. In the carriers of the 3.7 deletion, Red Blood Cells and Haematocrit were significantly increased. The Red Blood Cells were 7.23 ± 0.78 × 1012/L in adult males and 7.21 ± 0.67 × 1012/L in adult females while in children were 5.07 ± 0.87 × 1012/L. The mean cell volume and mean cell haemoglobin were significantly decreased, but the mean cell haemoglobin concentration slightly decreased. Haemoglobin levels didn't revealed statistically significant decrease in adult males (11.7 ± 0.57 g/dL) and adult females (11.25 ± 0.64 g/dL), while in children were (11.6 ± 2.95 g/dL). Haemoglobin electrophoresis revealed two patients of the 3.7 and 4.2 negative were carriers for β-thalassemia. The study concluded that α3.7 deletion has frequency of 0.07 in Sudanese with hypochromasia and microcytosis.

Matched MeSH terms: alpha-Thalassemia/diagnosis*
Molecular defects in the beta-globin gene identified in different ethnic groups/populations during prenatal diagnosis for beta-thalassemia: a Malaysian experience

Tan JA, George E, Tan KL, Chow T, Tan PC, Hassan J, et al.

Clin Exp Med, 2004 Dec;4(3):142-7.
PMID: 15599663 DOI: 10.1007/s10238-004-0048-x

Beta-thalassemia is the most-common genetic disorder of hemoglobin synthesis in Malaysia, and about 4.5% of the population are heterozygous carriers of the disorder. Prenatal diagnosis was performed for 96 couples using the Amplification Refractory Mutation System and Gap-Polymerase Chain Reaction. We identified 17 beta-globin defects-initiation codon for translation (T-G), -29 (A-G), -28 (A-G), CAP +1 (A-C), CD 8/9 (+G), CD 15 (G-A), CD 17 (A-T), CD 19 (A-G), Hb E (G-A), IVS1-1 (G-T), IVS1-5 (G-C), CD 41/42 (-CTTT), CD 71-72 (+A), IVS2-654 (CT), poly A(A-G), 100-kb Ggamma(Agammadeltabeta) degrees and 45-kb Filipino deletions. The 192 beta-alleles studied comprised Chinese (151 patients), Malay (21), Orang Asli from East Malaysia (15), Filipino (1), Indian (1), Indonesian Chinese (2), and Thai (1). In the Chinese, 2 beta-globin defects at CD 41/42 and IVS2-654 were responsible for 74% of beta-thalassemia. beta-mutations at CD 19, IVS1-1 (G-T), IVS1-5, poly A, and hemoglobin E caused 76% of the hemoglobin disorders in the Malays. The Filipino 45-kb deletion caused 73.3% of bthalassemia in the Orang Asli. Using genomic sequencing, the rare Chinese beta-mutation at CD 43 (G-T) was confirmed in 2 Chinese, and the Mediterranean mutation IVS1-1 (G-A) was observed in a Malay beta-thalassemia carrier. The beta-globin mutations confirmed in this prenatal diagnosis study were heterogenous and 65 (68%) couples showed a different globin defect from each other. The use of specific molecular protocols has allowed rapid and successful prenatal diagnosis of beta-thalassemia in Malaysia.

Matched MeSH terms: beta-Thalassemia/diagnosis*
Molecular heterogeneity of beta-thalassaemia in Malaysia: a practical approach to diagnosis

Thong MK, Law HY, Ng IS

Ann Acad Med Singap, 1996 Jan;25(1):79-83.
PMID: 8779552

The beta-thalassaemia mutations in 20 Malaysian children with beta-thalassaemia major were characterised by using a multi-modal approach, consisting of a slot-blot hybridisation with selected allele-specific oligonucleotides (ASO), followed by reverse dot-blot assay (RDB), amplification refractory mutation system (ARMS) and genomic sequencing. This strategy yielded a 94.4% mutation detection rate. The 6 most common mutations were codons 41/42 (-TTCT), IVS II nt 654(C --> T), IVS I nt 5(G --> C), IVS I nt 1(G -->T), codon 35 (-C) and codon 19 (A --> G), which accounted for 83.3% of all mutations detected. A strategy of initial screening with the above 6 selected ASOs for slot-blot hybridisation followed by RDB assay for the less common Asian mutations would give a mutation identification of 91.7%. Another feasible approach would be to analyse alleles from a particular racial group, by a judicious selection of 4 ASOs common to that particular subpopulation and then supplement this with RDB assay. This could yield a 100% coverage for the Chinese subpopulation in Malaysia. With these strategies, a practical approach has been identified to overcome the pitfalls posed by the molecular heterogeneity of beta-thalassaemia to enable prenatal diagnosis and carrier screening to be carried out. Regional collaborative studies are to be encouraged as an indispensable tool in providing better health care services to our patients.

Matched MeSH terms: beta-Thalassemia/diagnosis
Heterogeneity in alpha-thalassemia interactions in Malays, Chinese and Indians in Malaysia

Wee YC, Tan KL, Chow TW, Yap SF, Tan JA

J Obstet Gynaecol Res, 2005 Dec;31(6):540-6.
PMID: 16343256 DOI: 10.1111/j.1447-0756.2005.00333.x

AIM: Interactions between different determinants of alpha-thalassemia raises considerable problems, particularly during pregnancies where antenatal diagnosis is necessary. This study aims to determine the different types of deletional alpha-thalassemia and Hemoglobin Constant Spring (HbCS), and their frequency in Malays, Chinese and Indians in Malaysia.
METHODS: DNA from 650 pregnant women from the Antenatal Clinic of the University of Malaya Medical Center in Kuala Lumpur, Malaysia who showed mean cell volume < or =89 fL and/or mean cell hemoglobin < or =28 pg were analyzed for the double alpha-globin gene South-East Asian deletion (--SEA), the -alpha3.7 and -alpha4.2 single alpha-globin gene deletions and HbCS.
RESULTS: One hundred and three (15.8%) of the pregnant women were confirmed as alpha-thalassemia carriers: 25 (3.8%) were alpha-thalassemia-1 carriers with the --SEA/alphaalpha genotype, 64 (9.8%) were heterozygous for the -alpha3.7 rightward deletion (-alpha3.7/alphaalpha), four (0.6%) were heterozygous for the -alpha4.2 leftward deletion (-alpha4.2/alphaalpha), nine (1.4%) were heterozygous for HbCS (alphaCSalpha/alphaalpha) and one (0.2%) was compound heterozygous with the -alpha3.7/alphaCSalpha genotype. The double alpha-globin gene --SEA deletion was significantly higher in the Chinese (15%) compared to the Malays (2.5%) and not detected in the Indians studied. The -alpha3.7 deletion was distributed equally in the three races. HbCS and -alpha4.2 was observed only in the Malays.
CONCLUSION: The data obtained gives a better understanding of the interactions of the different alpha-thalassemia determinants in the different ethnic groups, thus enabling more rapid and specific confirmation of alpha-thalassemia in affected pregnancies where antenatal diagnosis is necessary.
Study site: Antenatal clinic, University Malaya Medical Centre (UMMC), Kuala Lumpur, Malaysia

Matched MeSH terms: alpha-Thalassemia/diagnosis
Counseling for prenatal diagnosis and termination of pregnancy due to thalassemia major: a survey of health care workers' practices in Malaysia

Ngim CF, Lai NM, Ibrahim H

Prenat Diagn, 2013 Dec;33(13):1226-32.
PMID: 24014379 DOI: 10.1002/pd.4233

OBJECTIVE: Genetic counseling for thalassemia carriers is conducted by nongeneticist health care workers (HCWs) in many countries. The aim of the study was to assess Malaysian HCWs' genetic counseling practices with regards to discussing prenatal diagnosis (PND) and termination of pregnancy (TOP) when counseling thalassemia carriers.
METHOD: A total of 118 Malaysian HCWs (52 doctors and 66 nurses) completed a structured questionnaire that enquired if they would discuss PND and TOP when counseling couples with thalassemia traits, and reasons for their responses were explored.
RESULTS: All the nurses and 50 (96.1%) doctors were in favor of discussing PND. Only 29 (58%) doctors and 33 (50%) nurses were agreeable to discuss about the option of TOP. Main reasons given for declining to discuss TOP were views that "the condition was not serious enough" (54.9%), TOP is not permissible by their religion (17.6%) and abortion for this indication was illegal (13.7%).
CONCLUSION: The results showed that HCWs in Malaysia lacked the comprehensive information and necessary skills required when counseling thalassemia carriers. When nongeneticist HCWs are tasked with such responsibilities, their practices and attitudes should be regularly evaluated so that areas of deficiencies could be identified and addressed.

Matched MeSH terms: beta-Thalassemia/diagnosis*
Genotype-Phenotype Correlation of β-Thalassemia in Malaysian Population: Toward Effective Genetic Counseling

Abdullah UYH, Ibrahim HM, Mahmud NB, Salleh MZ, Teh LK, Noorizhab MNFB, et al.

Hemoglobin, 2020 May;44(3):184-189.
PMID: 32586164 DOI: 10.1080/03630269.2020.1781652

Effective prevention of β-thalassemia (β-thal) requires strategies to detect at-risk couples. This is the first study attempting to assess the prevalence of silent β-thal carriers in the Malaysian population. Hematological and clinical parameters were evaluated in healthy blood donors and patients with β-thal trait, Hb E (HBB: c.79G>A)/β-thal and β-thal major (β-TM). β-Globin gene sequencing was carried out for 52 healthy blood donors, 48 patients with Hb E/β-thal, 34 patients with β-TM and 38 patients with β-thal trait. The prevalence of silent β-thal carrier phenotypes found in 25.0% of healthy Malaysian blood donors indicates the need for clinician's awareness of this type in evaluating β-thal in Malaysia. Patients with β-TM present at a significantly younger age at initial diagnosis and require more blood transfusions compared to those with Hb E/β-thal. The time at which genomic DNA was extracted after blood collection, particularly from patients with β-TM and Hb E/β-thal, was found to be an important determinant of the quality of the results of the β-globin sequencing. Public education and communication campaigns are recommended as apparently healthy individuals have few or no symptoms and normal or borderline hematological parameters. β-Globin gene mutation characterization and screening for silent β-thal carriers in regions prevalent with β-thal are recommended to develop more effective genetic counseling and management of β-thal.

Matched MeSH terms: beta-Thalassemia/diagnosis
Fulltext Predictive SNPs for β0-thalassemia/HbE disease severity

Munkongdee T, Tongsima S, Ngamphiw C, Wangkumhang P, Peerapittayamongkol C, Hashim HB, et al.

Sci Rep, 2021 05 14;11(1):10352.
PMID: 33990643 DOI: 10.1038/s41598-021-89641-2

β-Thalassemia/HbE disease has a wide spectrum of clinical phenotypes ranging from asymptomatic to dependent on regular blood transfusions. Ability to predict disease severity is helpful for clinical management and treatment decision making. A thalassemia severity score has been developed from Mediterranean β-thalassemia patients. However, different ethnic groups may have different allele frequency and linkage disequilibrium structures. Here, Thai β0-thalassemia/HbE disease genome-wild association studies (GWAS) data of 487 patients were analyzed by SNP interaction prioritization algorithm, interacting Loci (iLoci), to find predictive SNPs for disease severity. Three SNPs from two SNP interaction pairs associated with disease severity were identifies. The three-SNP disease severity risk score composed of rs766432 in BCL11A, rs9399137 in HBS1L-MYB and rs72872548 in HBE1 showed more than 85% specificity and 75% accuracy. The three-SNP predictive score was then validated in two independent cohorts of Thai and Malaysian β0-thalassemia/HbE patients with comparable specificity and accuracy. The SNP risk score could be used for prediction of clinical severity for Southeast Asia β0-thalassemia/HbE population.

Matched MeSH terms: beta-Thalassemia/diagnosis*