Population-Based Genetic Study of β-Thalassemia Mutations in Mardan Division, Khyber Pakhtunkhwa Province, Pakistan (original) (raw)
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This study aimed at the identification of the spectrum of mutations in patients with β-thalassemia (β-thal) in the western province of Saudi Arabia. Screening for the mutations was done using the polymerase chain reaction-amplification refractory mutation system (PCR-ARMS) technique to test for 12 mutations, and direct automated DNA sequencing for the unknown samples. The study included 172 patients; of these 15 patients had sickle cell anemia and one Hb S [β6 (A3)Glu→Val, GAG>GTG] /β-thal. A total of 23 mutations were identified to cause the disease in the western area. Seven common mutations were responsible for the β-thal alleles in 78% of patients and could be detected by the ARMS technique: IVS-II-1 (G>A), IVS-I-110 (G>A), IVS-I-5 (G>C), codon 39 (C>T), codon 26 (G>A) [Hb E or β26 (B8) Glu→Lys, GAG>AAG], frameshift codons (FSC) 8/9 (+G), and IVS-I-1 (G>A). DNA sequencing of uncharacterized alleles detected eight less common mutations: FSC 41/42 (–TCTT), IVS-I 25 bp deletion, codon 37 (G>A), FSC 44 (–C), Cap site +1 (A>C), IVS-I-6 (T>C), FSC 5 (–CT) and IVS-I-1 (G>T), and eight rare mutations: −87 (C>G), initiation codon −1 (T>G), codon 15 (G>A), FSC 16 (–C), FSC 20/21 (+G), codon 27 (G>A), IVS-I-130 (G>C) and IVS-II-837 (A>C). Four alleles were normal by DNA sequencing. Genetic heterogeneity was observed in this study, 10 mutations were of Asian or Asian/Indian origin, two were Kurdish, one Chinese, one Turkish, one Saudi, and the remainder were of Mediterranean origin. The presence of a large population of immigrants in the western province is responsible for the great heterogeneity at the molecular level, and for the difference observed in the frequencies of mutations from those reported in the eastern province of Saudi Arabia. Screening for β-thal mutations using PCR-ARMS for the seven most frequent mutations in the Saudi population followed by DNA sequencing of the unknown alleles could be useful for the implementation of a strategy for carrier detection and pre-implantation genetic diagnosis in high risk families.
Molecular epidemiology of β-thalassemia in pakistan: Far reaching implications
Indian Journal of Human Genetics, 2012
β-thalassaemia, an autosomal recessive hemoglobinopathy, is one of the commonest genetically transmitted disorders throughout the world. Collective measures including carrier identification, genetic counseling and prenatal diagnosis are required for preventing β-thalassemia. To achieve this objective, Identification of the spectrum of genetic mutations, especially for various ethnic backgrounds in Pakistan is necessary. Therefore, we designed a cross sectional prospective study to identify the frequency of various gene mutations in different ethnic groups of Pakistan. Over a 5-year period, DNA from 648 blood samples [including specimens of chorionic villus sampling (CVS)] were analyzed for the twelve most common β-thalassemia mutations found in the Pakistani population by a Multiplex amplification refractory mutation system (ARMS). The most common mutation identified was Intervening Sequence 1-5 (IVS 1-5 (G-C)); accounting for 40.89% mutated alleles, and was represented in all ethnic groups. 15.7 % of the βthalassemia alleles were found to have Frameshift 8-9 (Fr 8-9) as the second most common mutation Other common genetic defects responsible for β-thalassemia: IVS 1-1 (G-T) was found in 8.17%, Codon-30 (Cd-30 (G-C)) 8.02%, Codon-5(Cd-5 (-CT)) contributed 2.16% and Deletion 619 base pair (Del 619bp) affected 11.11% were found in Pakistan. This large study adds to the pre-existing data in Pakistan. Knowledge of the predominant mutation in a given ethnic group will not only help in developing a short panel of (population-specific) primers of mutations thereby providing a cost-effective method for prenatal diagnosis and also help the clinicians to counsel regarding blood transfusion regimen/ pregnancy termination.
Hemoglobin, 2013
Both αand β-thalassemia (α-and β-thal) are highly prevalent in the population of the Al-Qatif and Al-Ahsa regions in the Eastern Province of Saudi Arabia. This study provides a more precise picture of the α-thal mutations prevalent in 104 transfusion-dependent β-thal patients in the Eastern Province. Detection of α-thal mutations was carried out using the α-globin StripAssay kit. A total of 12 α-thal mutations (21 genotypes) were identified in 33.7% of the chromosomes (46 patients). The heterozygous and homozygous -α 3.7 (α þ ) deletion mutations were the most prevalent in the β-thal patients (21.7%). We identified three α 0 deletions [--MED , --FIL and -(α)20.5] that have not been previously reported for the population of Saudi Arabia. The seven point mutations identified in the βthal patients were: codon 14 [TGG>TAG (α1)], codon 59 [GGC>GAC (α1)] (Hb Adana), polyadenylation signal site (polyA1) [AATAAA>AATAAG (α2)], codon 142 [TAA>TCA (α2)] (Hb Koya Dora), codon 59 [GGC>GAC (α2)] (Hb Adana), initiation codon [ATG>ACG (α2)] and the ααα anti 3.7 gene triplication. The Hb Koya Dora mutation occurred at the highest frequency (15. . Comparison of the clinical phenotype of β-thal patients, with and without an α-thal mutation, showed that patients with β-thal alone had a significantly elevated level of alanine transaminase (ALT) (mean 72.5 IU/L) and aspartate transaminase (AST) (mean 71.8 IU/L) (p <0.005). In addition, the β-thal patients without an α-thal mutation had a higher percentage of osteoporosis (16.6%), fractures (12.5%), and splenectomies (58.3%). This confirms previous data .in β-thal patients. Moreover, the high frequency of αand β-thal in the Eastern Province of Saudi Arabia and their coinheritance, necessitates the inclusion of α-thal testing in the current pre marital testing program to highlight the risk to the offspring of affected individuals.
Genetic diversity of beta-thalassemia mutations in Pakistani population
JPMA. The Journal of the Pakistan Medical Association, 2000
beta-thalassemia is one of the most common inherited single gene disorder in Pakistan. It is characterized by reduced or absent beta-globin gene expression resulting in abnormal maturation and survival of red blood cells. Due to high prevalence of this disease in the local population, it has become important for the health care providers to encourage people to utilize laboratory facilities for carrier and prenatal genetic testing. To study the frequency of beta-thalassemia mutations in Pakistani population. A tertiary care teaching hospital. Blood samples of 72 couples and chorionic villus (CV) biopsy specimen collected at the Aga Khan University Hospital, Karachi were tested by Amplified Refractory Mutation Systems (ARMS) for the 12 most common mutations in the beta-globin gene. Out of 72 chorionic villus biopsy specimen analyzed, 17 (23%) had mutations in both alleles of the beta-globin gene. Homozygosity was identified in 6 CV samples, whereas 11 CV specimens were diagnosed as do...
The Frequency of HBB Mutations Among β-Thalassemia Patients in Hamadan Province, Iran
Hemoglobin, 2017
b-Thalassemia (b-thal) caused by mutations on the HBB gene is the most common single-gene disorder in the world. In this study, the HBB gene mutation was investigated in Hamadan province, Iran. Fortyone patients referred to a referral hospital were admitted to the study. DNA samples were extracted from peripheral blood. The HBB gene was sequenced in all recruited patients. Eleven mutations and eight polymorphisms were found in the studied patients. IVS-II-1 (G>A) (HBB: c.315þ1 G>A) was the most common mutation, accounting for 25.61% of mutant alleles. Other mutations included codon 8 (-AA) (HBB: c.25À26delAA); IVS-I-110 (G>A) (HBB: c.93À21 G>A); codons 8/9 (þG) (HBB: c.27À28insG); IVS-I-1 (G>A) (HBB: c.92 G>A); codon 44 (-C) (HBB: c.135delC); codons 25/26 (þT) (HBB: c.78À79insT); IVS-I-130 (G>C) (HBB: c.93À1 G>C);-28 (A>C) (HBB: c.À78 A>C); codons 36/37 (-T) (HBB: c.112delT) and IVS-I-6 (T>C) (HBB: c.92þ6 T>C). According to our findings, the IVS-II-1 mutation has the highest prevalence in Hamadan Province. It was found that the total frequency of the IVS-II-1, codons 25/26 (þT), codons 8/9 (þG), IVS-I-110 and IVS-I-1 mutations was 82.92%. Therefore, given these findings, it is recommended that these five mutations are screened for as a first step in laboratories without sequencing instruments, and that the rest of the gene is subsequently examined.
Sultan Qaboos University medical journal, 2009
Thalassemia is one of the most common autosomal single-gene disorder worldwide. The highest prevalence of the disease is in the "thalassemia belt" which includes the Mediterranean region, parts of the Middle East, the Indian subcontinent, the southern parts of the Far East, Pakistan and South-East Asia. This study aimed to detect the common molecular abnormalities of the beta thalassemia syndrome in Pakistan. The study was conducted at the Institute of Hematology, Baqai Medical University, Karachi, Pakistan from August 2004 to November 2007. Blood samples of patients with beta thalassemia major (n = 400) were collected from hospital transfusion centres and diagnostic laboratories in different districts of Karachi representing five major ethnic groups including Punjabi, Pathan, Sindhi, Baluchi and Urdu speaking. All the samples were analysed for five common mutations by using the polymerase chain reaction technique ARMS (amplification of refractory mutation system). The dat...
Study of Mutations in β -Thalassemia Trait among Blood Donors in Eastern Uttar Pradesh
JOURNAL OF CLINICAL AND DIAGNOSTIC RESEARCH, 2013
Background: Knowledge on distribution of different mutations of thalassaemia, which are prevalent in a particular area, is a prerequisite for prenatal diagnosis. Objectives: Studying mutations in β-thalassaemia trait among blood donors in eastern Uttar Pradesh, India. Material and Methods: One thousand non-remunerated voluntary blood donors who were between 18-40 years of age, were included in the study. Both replacement and voluntary healthy blood donors were included. 4ml of venous blood was collected and it was stored at 4ºC. Complete Blood Count (CBC), Haemoglobinopathy Screening and Molecular Analysis by ARMS-PCR (Amplification Refractory Mutation System-PCR) were done. Screening for β thalassaemia was done in a blood bank by using D-10, Bio Rad, which was based on High Performance Liquid Chromatography (HPLC). Results: Twenty Eight subjects with β-thalassaemia trait were found among 1000 voluntary blood donors. IVS 1-5 (G-C) mutation was most common type (50%), followed by FS 8/9 (+G) 25% which was the second most common type. In our study, a rare mutation of CD 16 (-C) was also found. Out of 14 subjects who had IVS 1-5 (G-C) mutation (most common), six were from Varanasi (6/261) and five of them were Sindhis. It was seen that FS 41/42 (TCTT) mutation was distributed among all groups of populations which had higher prevalences of β-thalassaemia trait. Conclusion: A comprehensive knowledge on beta thalassaemia mutations is necessary for determining a prenatal diagnosis. The occurrence of mutations may vary according to geographic region. Therefore, this study dealt with current problem of unknown mutations, in order to avoid complications.