scholarly journals Prevalence and clinical phenotype of the triplicated α-globin genes and its ethnic and geographical distribution in Guizhou of China

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Xi Luo ◽  
Xiang-mei Zhang ◽  
Liu-song Wu ◽  
Jindong Chen ◽  
Yan Chen
Keyword(s):  
Genetic Counseling ◽  
Peripheral Blood ◽  
Clinical Phenotype ◽  
Globin Gene ◽  
Clinical Manifestations ◽  
Gene Mutations ◽  
Guizhou Province ◽  
Globin Genes ◽  
Phenotype Correlation ◽  
Chi Square

Abstract Background α-thalassemia is relatively endemic in Guizhou province of southwestern China. To predict the clinical manifestations of α-globin gene aberration for genetic counseling, we examined the prevalence of the α-globin triplication and the genotype–phenotype correlation in this subpopulation Methods A cohort of 7644 subjects was selected from nine ethnicities covering four regions in Guizhou province of China. Peripheral blood was collected from each participant for routine blood testing and hemoglobin electrophoresis. PCR-DNA sequencing and Gap-PCR were used to identify the thalassemia gene mutations. Chi-square tests and one-way analysis of variance (ANOVA) were used to statistically analyze the data. Results We found that the frequency of α-globin triplication in Guizhou province was 0.772% (59/7644). Genotypically, the αααanti4.2/αα accounted for 0.523% (40/7644), the αααanti3.7/αα for 0.235% (18/7644), and the αααanti3.7/–SEA for 0.013% (1/7644). The αααanti4.2/αα is more prevalent than the αααanti3.7/αα in Guizhou. In addition, the frequency of the HKαα/αα (that by GAP-PCR is like αααanti4.2/-α3.7) was 0.235% (18/7644). Ethnically, the Tujia group presented the highest prevalence (2.47%) of α-globin triplication. Geographically, the highest frequency of the α-globin triplication was identified in Qiannan region (2.23%). Of the triplicated α-globin cases, 5 coinherited with heterozygote β-thalassemia and presented various clinical manifestations of anemia. Conclusions These data will be used to update the Chinese triplicated α-globin thalassemia database and provide insights into the pathogenesis of thalassemia. These findings will be helpful for the diagnosis of thalassemia and future genetic counseling in those regions.

scholarly journals Prevalence and Clinical Phenotype of the Triplicated α-Globin Genes and its Ethnic and Geographical Distribution in Guizhou of China

2020 ◽  
Author(s):  
Xi Luo ◽  
Shi-ping Chen ◽  
Xiang-mei Zhang ◽  
Liu-song Wu ◽  
Zhi-yu Peng ◽  
...  
Keyword(s):  
Genetic Counseling ◽  
Peripheral Blood ◽  
Clinical Phenotype ◽  
Globin Gene ◽  
Clinical Manifestations ◽  
Gene Mutations ◽  
Guizhou Province ◽  
Globin Genes ◽  
Phenotype Correlation ◽  
Chi Square

Abstract Background: Thalassemia is relatively epidemic in Guizhou province of southwestern China. To predict the clinical manifestations of α-globin gene aberration for genetic counseling, we examined the prevalence of the α-globin triplication and the genotype-phenotype correlation in this subpopulationMethods: A cohort of 7644 subjects was collected from nine ethnicities covering four regions in Guizhou province of China. Peripheral blood was collected from each participant for routine blood testing and hemoglobin electrophoresis. PCR-DNA sequencing and Gap-PCR were used to identify the thalassemia gene mutations. Chi-square tests and one-way analysis of variance (ANOVA) were used to statistically analyze the data. Results: We found that the frequency of α-globin triplication in Guizhou province was 0.759% (58/7644). Genotypically, the αααanti4.2/αα accounted for 0.523% (40/7644), the αααanti3.7/αα for 0.235% (18/7644). The αααanti4.2/αα is more prevalent than the αααanti3.7/αα in Guizhou. In addition, the frequency of the αααanti4.2/-α3.7 (HK αα) was 0.235% (18/7644), and the αααanti3.7/--SEA was 0.013% (1/7644). Ethnically, the Tujia group presented the highest prevalence (2.47%) of α-globin triplication. Geographically, the highest frequency of the α-globin triplication was identified in Qiannan region (2.23%). Of the triplicated α-globin cases, 5 coinherited with heterozygote β-thalassemia and presented various clinical manifestations of anemia. Conclusions: These data will be used to update the triplicated α-globin thalassemia database and provide insights into the pathogenesis of thalassemia. These findings will be helpful for the diagnosis of thalassemia and future genetic counseling in those regions.

scholarly journals Genotype-phenotype correlation of HbH disease in northern Iraq

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Rawand P. Shamoon ◽  
Ahmed K. Yassin ◽  
Ranan K. Polus ◽  
Mohamad D. Ali
Keyword(s):  
Globin Gene ◽  
Gene Mutations ◽  
Globin Genes ◽  
Phenotype Correlation ◽  
Deletion Mutations ◽  
Northern Iraq ◽  
Screening And Prevention ◽  
First Time ◽  
Hbh Disease

Abstract Background HbH disease results from dysfunction of three, less commonly two, α-globin genes through various combinations of deletion and non-deletion mutations. Characterization of the mutations and the underlying genotypes is fundamental for proper screening and prevention of thalassaemia in any region. The aim of this study was to explore the genetic arrangements of HbH disease and to correlate the genotypes with the clinical phenotypes. Methods A total of 44 HbH disease patients were enrolled in this study. They were clinically and haematologically assessed. The patients were tested for 21 common α-globin gene mutations using multiplex PCR and reverse hybridization. According to the genotype, the patients were categorized into two separate sub-groups, deletion and non-deletion types HbH disease. Results Within the studied HbH disease patients, eight different α-globin gene mutations were detected in nine different genetic arrangements. The --MED and -α3.7 deletions were the two most frequently encountered mutations (37.5 and 35.2% respectively). Patients with deletion genotypes constituted 70.4%. The most common detected genotype was --MED/−α3.7 (59.1%), followed by αpoly-A1α/αpoly-A1α (13.6%). For the first time, coinheritance of two relatively mild mutations (−α3.7/ααAdana) was unpredictably detected in a 1.5 year-old child with Hb of 7.1 g/dL. Conclusion The HbH disease patients’ clinical characteristics were variable with no ample difference between the deletion and non-deletion types. These results can be of benefit for the screening and management of thalassaemia in this region.

scholarly journals Genotype-Phenotype Correlation of HbH Disease in Northern Iraq

2020 ◽  
Author(s):  
Rawand P Shamoon ◽  
Ahmed K Yassin ◽  
Ranan K Polus ◽  
Mohamed D DaherAli
Keyword(s):  
Globin Gene ◽  
Gene Mutations ◽  
Globin Genes ◽  
Phenotype Correlation ◽  
Deletion Mutations ◽  
Northern Iraq ◽  
Screening And Prevention ◽  
First Time ◽  
Hbh Disease

Abstract Background: HbH disease results from dysfunction of three, less commonly two, α-globin genes through various combinations of deletion and non-deletion mutations. Characterization of the mutations and the underlying genotypes is fundamental for proper screening and prevention of thalassaemia in any region. The aim of this study was to explore the genetic arrangements of HbH disease and to correlate the genotypes with the clinical phenotypes.Method: A total of 44 HbH disease patients were enrolled in this study. They were clinically and haematologically assessed. The patients were tested for 21 common α-globin gene mutations using multiplex PCR and reverse hybridization. According to the genotype, the patients were categorized into two separate sub-groups, deletion and non-deletion types HbH disease. Results: Within the studied HbH disease patients, eight different α-globin gene mutations were detected in nine different genetic arrangements. The --MED and -α3.7 deletions were the two most frequently encountered mutations (37.5% and 35.2% respectively). Patients with deletion genotypes constituted 70.4%. The most common detected genotype was --MED/-α3.7 (59.1%), followed by αpoly-A1α/αpoly-A1α (13.6%). For the first time, coinheritance of two relatively mutations (-α3.7/ααAdana) was unpredictably detected in a 1.5 year-old child with Hb of 7.1 g/dL. Conclusion: The HbH disease patients’ clinical characteristics were variable with no ample difference between the deletion and non-deletion types. These results can be of benefit for the screening and management of thalassaemia in this region.

scholarly journals Genotype-Phenotype Correlation of HbH Disease in Northern Iraq

2020 ◽  
Author(s):  
Rawand P Shamoon ◽  
Ahmed K Yassin ◽  
Ranan K Polus ◽  
Mohamed D DaherAli
Keyword(s):  
Globin Gene ◽  
Gene Mutations ◽  
Globin Genes ◽  
Phenotype Correlation ◽  
Deletion Mutations ◽  
Northern Iraq ◽  
Screening And Prevention ◽  
First Time ◽  
Hbh Disease

Abstract Background: HbH disease results from dysfunction of three, less commonly two, α-globin genes through various combinations of deletion and non-deletion mutations. Characterization of the mutations and the underlying genotypes is fundamental for proper screening and prevention of thalassaemia in any region. The aim of this study was to explore the genetic arrangements of HbH disease and to correlate the genotypes with the clinical phenotypes.Methods: A total of 44 HbH disease patients were enrolled in this study. They were clinically and haematologically assessed. The patients were tested for 21 common α-globin gene mutations using multiplex PCR and reverse hybridization. According to the genotype, the patients were categorized into two separate sub-groups, deletion and non-deletion types HbH disease. Results: Within the studied HbH disease patients, eight different α-globin gene mutations were detected in nine different genetic arrangements. The --MED and -α3.7 deletions were the two most frequently encountered mutations (37.5% and 35.2% respectively). Patients with deletion genotypes constituted 70.4%. The most common detected genotype was --MED/-α3.7 (59.1%), followed by αpoly-A1α/αpoly-A1α (13.6%). For the first time, coinheritance of two relatively mild mutations (-α3.7/ααAdana) was unpredictably detected in a 1.5 year-old child with Hb of 7.1 g/dL. Conclusion: The HbH disease patients’ clinical characteristics were variable with no ample difference between the deletion and non-deletion types. These results can be of benefit for the screening and management of thalassaemia in this region.

Significance of genetic counseling and prenatal diagnosis on α2 codon 30 (-GAG) (HBA2: c.91_93delGAG) mutation

2019 ◽  
Author(s):  
Zhiyang Guan ◽  
Zeyan Zhong ◽  
Hailin He ◽  
Dan Chen ◽  
Guoxing Zhong ◽  
...  
Keyword(s):  
Genetic Counseling ◽  
Prenatal Diagnosis ◽  
Dna Analysis ◽  
Globin Gene ◽  
Gene Mutations ◽  
Severe Form ◽  
Clinical Severity ◽  
Globin Genes ◽  
Significant Difference ◽  
Hb H Disease

Abstract Background : Non-deletional hemoglobin (Hb) H disease is the severest form of α- thalassemia ( thal ) compatible with post-natal life, which is caused by the interaction of an α-globin gene mutation with α 0 -thal. Therefore, it is important to identify rare α-globin gene mutations for the prevention of severe form of non-deletional Hb H disease . Methods: In all, 61,796 samples were characterized at our center. Common α- and β- thalassemia mutations were detected by routine DNA analysis (gap-PCR and PCR-RDB ). The DNA sequencing of α-globin genes was performed to identify the unknown mutation. Statistical analyses were conducted using SPSS 19.0 statistical software. Results: Of the 61,796 samples, eight were identified as α2 codon 30 (-GAG) ( HBA2 : c.91_93delGAG) mutation s, and of these, four had coinheritance with - - SEA deletion Patients with the heterozygous α2 codon 30 (-GAG) ( HBA2 : c.91_93delGAG) mutation had significantly lower levels of MCV and MCH than healthy individuals ( p < 0.01), and coinheritance with - - SEA deletion aggravated the α-thal phenotype , associated with severe Hb H disease . Moreover, a significant difference in the clinical severity was found in the Hb H disease patients with the same genotype.Conclusions: This finding is of great significance for clinicians to provide accurate genetic counseling , particularly prenatal diagnosis and establish a rigorous diagnostic procedure .

scholarly journals Genotype-Phenotype Correlation of HbH Disease in Northern Iraq

2020 ◽  
Author(s):  
Rawand P Shamoon ◽  
Ahmed K Yassin ◽  
Ranan K Polus ◽  
Mohamed D DaherAli
Keyword(s):  
Globin Gene ◽  
Gene Mutations ◽  
Globin Genes ◽  
Phenotype Correlation ◽  
Deletion Mutations ◽  
Northern Iraq ◽  
Screening And Prevention ◽  
First Time ◽  
Hbh Disease

Abstract Background: HbH disease results from dysfunction of three, less commonly two, α-globin genes through various combinations of deletion and non-deletion mutations. Characterization of the mutations and the underlying genotypes is fundamental for proper screening and prevention of thalassaemia in any region. The aim of this study was to explore the genetic arrangements of HbH disease and to correlate the genotypes with the clinical phenotypes.Methods: A total of 44 HbH disease patients were enrolled in this study. They were clinically and haematologically assessed. The patients were tested for 21 common α-globin gene mutations using multiplex PCR and reverse hybridization. According to the genotype, the patients were categorized into two separate sub-groups, deletion and non-deletion types HbH disease. Results: Within the studied HbH disease patients, eight different α-globin gene mutations were detected in nine different genetic arrangements. The --MED and -α3.7 deletions were the two most frequently encountered mutations (37.5% and 35.2% respectively). Patients with deletion genotypes constituted 70.4%. The most common detected genotype was --MED/-α3.7 (59.1%), followed by αpoly-A1α/αpoly-A1α (13.6%). For the first time, coinheritance of two relatively mild mutations (-α3.7/ααAdana) was unpredictably detected in a 1.5 year-old child with Hb of 7.1 g/dL. Conclusion: The HbH disease patients’ clinical characteristics were variable with no ample difference between the deletion and non-deletion types. These results can be of benefit for the screening and management of thalassaemia in this region.

scholarly journals Proximal Myopathy due to m.5835G>A Mutation in Mitochondrial MT-TY Gene

2018 ◽  
Vol 2018 ◽  
pp. 1-4 ◽  
Author(s):  
C. Simoncini ◽  
V. Montano ◽  
G. Alì ◽  
R. Costa ◽  
G. Siciliano ◽  
...  
Keyword(s):  
Clinical Phenotype ◽  
Gene Mutations ◽  
Mitochondrial Diseases ◽  
Leigh Syndrome ◽  
Phenotype Correlation ◽  
Mitochondrial Trna ◽  
Gene Coding ◽  
Clinical Presentations ◽  
Wide Range ◽  
Proximal Myopathy

Mitochondrial (mt) tRNA (MTT) gene mutations are an important cause of mitochondrial diseases and are associated with a wide range of clinical presentations. Most mutations fall into three mitochondrial tRNAs (tRNAIle, tRNALeu (UUR), and tRNALys) and are responsible for half of the mitochondrial diseasees associated with tRNA mutation, with MERRF, MELAS, mitochondrial myopathy, and Leigh syndrome being the most frequent phenotypes. More than 100 tRNA pathogenetic mutations are described, showing little correlation between the observed clinical phenotype and a specific mitochondrial tRNA mutation. Furthermore different mutation can manifest with similar clinical phenotypes, making the genotype-phenotype correlation difficult. Here we report the case of an Italian 53-year-old woman presenting with a proximal myopathy and the m.5835G>A mutation in MT-TY gene coding for the mitochondrial tRNA Tyrosine gene.

scholarly journals Clinical Features and Molecular Analysis of Hb H Disease in Taiwan

2014 ◽  
Vol 2014 ◽  
pp. 1-5
Author(s):  
Yu-Hua Chao ◽  
Kang-Hsi Wu ◽  
Han-Ping Wu ◽  
Su-Ching Liu ◽  
Ching-Tien Peng ◽  
...  
Keyword(s):  
Clinical Features ◽  
Globin Gene ◽  
Clinical Manifestations ◽  
Clinical Severity ◽  
Blood Transfusions ◽  
Limited Data ◽  
Phenotype Correlation ◽  
Younger Age ◽  
Hb H Disease ◽  
Thalassemia Mutation

Thalassemia is highly prevalent in Taiwan, but limited data are available about the association between genotypes and clinical manifestations in Taiwanese patients with Hb H disease. Here, we studied α-globin gene abnormalities and clinical features in Taiwanese patients with Hb H disease. Of the 90 patients, sixty-four (71.1%) were deletional and twenty-six (28.9%) were nondeletional Hb H disease. The (- -SEA) type ofα0-thalassemia mutation was detected in the majority of patients (>95%). The most common genotype was (- -SEA/-α3.7), followed by (- -SEA/αcsα). After further investigation of the genotype-phenotype correlation in 68 patients, we found that patients with nondeletional Hb H disease had more severe clinical features than those with deletional Hb H disease, including younger age at diagnosis, more requirement of blood transfusions, and larger proportion of patients with splenomegaly, hepatomegaly or jaundice. This is probably a consequence of the lower hemoglobin levels and the higher Hb H levels. The clinical severity was highly variable even among patients with an identical genotype, and the diversity was much more profound among patients with (- -/αcsα) genotype. Therefore, predicting the phenotype directly from the genotype in Hb H disease remains relatively difficult in Taiwan.

scholarly journals Hypomethylation of DNA derived from purified human erythroid cells correlates with gene activity of the beta-globin cluster

Blood ◽  
1985 ◽  
Vol 66 (5) ◽  
pp. 1202-1207 ◽  
Author(s):  
A Oppenheim ◽  
Y Katzir ◽  
E Fibach ◽  
A Goldfarb ◽  
E Rachmilewitz
Keyword(s):  
Peripheral Blood ◽  
Globin Gene ◽  
Genetic Regulation ◽  
Inverse Correlation ◽  
Thalassemia Major ◽  
Gene Activity ◽  
Beta Thalassemia ◽  
Globin Genes ◽  
Beta Globin ◽  
A Site

Abstract Analysis of methylation at the beta-globin gene cluster was carried out on DNA derived from nucleated RBCs (orthochromatic normoblasts) isolated from peripheral blood of patients with beta-thalassemia major or other congenital hemolytic anemia after splenectomy. A procedure to separate these normoblasts from the other nucleated cells of the peripheral blood was developed, providing us with a convenient source of DNA for investigating parameters related to human erythroid differentiation. Blood samples were obtained from six adult patients who express their gamma-globin genes at different levels. Inverse correlation between methylation and gene activity was consistently observed for five of the eight sites analyzed. A site 3′ to the beta gene was always unmethylated, two sites flanking the epsilon gene were always found to be methylated, and two sites 5′ to the two gamma genes, G gamma and A gamma, were hypomethylated in correlation with gamma gene activity of the individual patients. A site 5′ to the delta gene was unmethylated in normoblasts as well as in WBC. No apparent relation between hypomethylation and gene activity was observed for two additional sites. The results suggest that methylation at specific chromosomal locations participate in genetic regulation of the beta- like globin genes in humans.

Two Distinct Genetic Mechanisms Modify the Level of HbA2 in Peripheral Blood,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3193-3193
Author(s):  
Swee Lay Thein ◽  
Chad P. Garner ◽  
Tim D Spector ◽  
Stephan Menzel
Keyword(s):  
Gene Expression ◽  
Peripheral Blood ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Globin Genes ◽  
Nucleotide Polymorphisms ◽  
Beta Globin ◽  
Erythroid Progenitors ◽  
Genome Wide ◽  
F Cells

Abstract Abstract 3193 The switch from embryonic to fetal hemoglobin (HbF, α2γ2) in utero, and from fetal to adult hemoglobin at birth is well documented and achieved by the sequential activation of ε, γ and δ/β genes at the β globin gene (HBB) cluster. A change in the expression of hemoglobin genes also take place in adult erythropoiesis: earlier erythroid progenitors have been shown to produce significant amounts of fetal hemoglobin, while the more mature progenitors contain essentially none. In keeping with the sequential activation of β-like globin genes, δ globin chain synthesis also declines as maturation in erythroid progenitors progresses. Understanding the developmental changes of gene expression at the beta globin locus is not purely of academic interest, since a therapeutic induction of HbF or HbA2 (α2δ2) production would be of significant clinical benefit for patients with a defect of HbA (α2β2) function or abundance, such as sickle cell disease or β thalassemia. We have previously studied the genetic regulation of fetal hemoglobin persistence in a genome-wide association study (GWAS) in healthy volunteers, and are now extending this approach to the study of HbA2. Our study population is the 'Twins UK' twin registry of healthy Europeans, mostly female adult individuals, with genome-wide single polymorphisms (SNP) data and hemoglobin phenotypes for a primary study group (n=2,340) and a second replication group (n=1,880). A quantitative trait GWAS analysis was carried out to assess the relationship between SNPs and the HbA2 trait. We found that HbA2 (as a percentage of total hemoglobin) was weakly, but significantly, correlated with the amount of fetal hemoglobin carrying cells (F cells) an individual possesses (r = 0.14, p < 0.01). This suggests the existence of some common biological process that influences both hemoglobin species. We also found that the same SNP alleles at chromosome 6q23.3 (HBS1L-MYB, peak signal rs7775698, p = 2.51×10−9) that are associated with a boost in the prevalence of F cells and larger red blood cells (denoted by the mean cell volume or MCV) also promote HbA2 levels, again pointing to some common biological factor connected with the erythropoietic maturation process. Interestingly, neither of the other two major HbF loci, BCL11A on chromosome 2p, or the HbF-promoting regions within the HBB cluster (at the β LCR and the γ globin genes) on chromosome 11p, showed association with HbA2 levels. Instead, SNPs around the β globin gene itself (clearly separate also from the delta gene) exert a significant influence on HbA2 levels (peak association rs12793110, p=5.11×10−12) (see Figure 1). In contrast to the HBS1L-MYB region on chromosome 6, the HbA2-boosting alleles at these SNPs do not increase red blood cell MCV. We propose that the SNPs around HBB influences HbA2 (ie. δ globin gene) expression via a mechanism that is related to the competitive process between the β and δ gene expression that might mimic a very mild β thalassemic effect. Figure 1: Association with single-nucleotide polymorphisms (SNP) near the beta globin gene cluster on chromosome 11p15.4 with abundance of HbA2 (filled circles ¥) and F cells (empty circles ○) in the peripheral blood of Northern European adults (Twins UK). Figure 1:. Association with single-nucleotide polymorphisms (SNP) near the beta globin gene cluster on chromosome 11p15.4 with abundance of HbA2 (filled circles ¥) and F cells (empty circles ○) in the peripheral blood of Northern European adults (Twins UK). We propose that the systematic genetic study of specialized hematological traits in healthy volunteers can help to understand the biology of hematopoiesis. Disclosures: No relevant conflicts of interest to declare.

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