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Genome Medicine Feb 2021Noninvasive prenatal testing (NIPT) of recessive monogenic diseases depends heavily on knowing the correct parental haplotypes. However, the currently used family-based...
BACKGROUND
Noninvasive prenatal testing (NIPT) of recessive monogenic diseases depends heavily on knowing the correct parental haplotypes. However, the currently used family-based haplotyping method requires pedigrees, and molecular haplotyping is highly challenging due to its high cost, long turnaround time, and complexity. Here, we proposed a new two-step approach, population-based haplotyping-NIPT (PBH-NIPT), using α-thalassemia and β-thalassemia as prototypes.
METHODS
First, we deduced parental haplotypes with Beagle 4.0 with training on a large retrospective carrier screening dataset (4356 thalassemia carrier screening-positive cases). Second, we inferred fetal haplotypes using a parental haplotype-assisted hidden Markov model (HMM) and the Viterbi algorithm.
RESULTS
With this approach, we enrolled 59 couples at risk of having a fetus with thalassemia and successfully inferred 94.1% (111/118) of fetal alleles. We confirmed these alleles by invasive prenatal diagnosis, with 99.1% (110/111) accuracy (95% CI, 95.1-100%).
CONCLUSIONS
These results demonstrate that PBH-NIPT is a sensitive, fast, and inexpensive strategy for NIPT of thalassemia.
Topics: Genetics, Population; Haplotypes; Humans; Noninvasive Prenatal Testing; Parents; Sample Size; alpha-Thalassemia; beta-Thalassemia
PubMed: 33546747
DOI: 10.1186/s13073-021-00836-8 -
Hemoglobin Jan 2022Bangladesh is a country with a population of 160 million with a gross national income per capita of US$1580.00. The major health problems in Bangladesh include acute... (Review)
Review
Bangladesh is a country with a population of 160 million with a gross national income per capita of US$1580.00. The major health problems in Bangladesh include acute respiratory infection, pneumonia, dengue fever, malaria and water-borne diseases. The health care system in Bangladesh is divided into primary secondary and tertiary levels, with each level having their own breakdown of available hospital beds and other treatment facilities. Thalassemia is a major health problem in Bangladesh. There are two types of thalassemia in Bangladesh: β-thalassemia (β-thal) and Hb E (: c.79G>A)/β-thal, with the prevalence rate of β-thal trait being 4.1% and Hb E trait 6.1%. This study discusses spectrum types of thalassemia and hemoglobinopathies in Bangladesh and the types of carrier detection. The distribution of common mutations of thalassemia are also discussed and the distribution frequencies of genotypes and alleles of β-thal and Hb E patients are also compared. Additionally, we also conducted a study of the spectrum of thalassemia using high performance liquid chromatography (HPLC) of the tribal populations and analyzed the findings in our discussion. The results of these studies show that the phenotypic and genotypic presentation in Bangladesh is highly diverse. To properly understand this, we have to conduct an epidemiological survey of the population. Furthermore, there also has to be improvement on the awareness of thalassemia among the population to properly equip themselves to survive this disease.
Topics: Asia; Bangladesh; Hemoglobinopathies; Humans; Mutation; alpha-Thalassemia; beta-Thalassemia
PubMed: 35950585
DOI: 10.1080/03630269.2021.2008957 -
Hemoglobin May 2022Despite several studies performed in different provinces of Iran to identify the spectrum of α-globin gene mutations, no such study has so far been carried out in Ilam...
Despite several studies performed in different provinces of Iran to identify the spectrum of α-globin gene mutations, no such study has so far been carried out in Ilam Province. A total of 274 individuals, including 201 α-thalassemia (α-thal) carriers and 73 normal subjects, originating from the northern counties of Ilam Province, participated in this study. Analysis of α-globin defects was performed using multiplex gap-polymerase chain reaction (gap-PCR), amplification refractory mutation system (ARMS)-PCR and direct sequencing, which revealed a total of 11 different mutations and 22 different genotypes. The -α (rightward) (NG_000006.1: g.34164_37967del3804), αα (: c.95 + 2_95 + 6delTGAGG), and -α (leftward) deletions were the most prevalent mutations identified in our study, with frequencies of 66.23, 10.09 and 8.33%, respectively. In conclusion, the present study showed that the α-thal mutation spectrum in Ilam Province, at least in the northern part of the province, is different from that in other geographical regions of Iran. These results increase our knowledge about the spectrum and distribution of α-globin gene mutations in Iran.
Topics: Gene Frequency; Genotype; Heterozygote; Humans; Iran; Mutation; alpha-Globins; alpha-Thalassemia
PubMed: 32072847
DOI: 10.1080/03630269.2019.1694033 -
Molecular and Hematological Analysis of Alpha- and Beta-Thalassemia in a Cohort of Mexican Patients.Genetic Testing and Molecular Biomarkers Mar 2021Alpha- and beta-thalassemia are caused by reduced or absent synthesis of hemoglobin (Hb) subunits α and/or β. , , and mutations are the main cause of thalassemias....
Alpha- and beta-thalassemia are caused by reduced or absent synthesis of hemoglobin (Hb) subunits α and/or β. , , and mutations are the main cause of thalassemias. The aim of this article is to analyze molecular and hematological features of α- and β-thal in a cohort of Mexican patients. One hundred forty-one thalassemia patients were studied. Peripheral blood was collected for blood cell count, electrophoresis, Hb quantification, and molecular testing. Molecular screening was performed by Gap-PCR, ARMS-PCR, Sanger sequencing, and MLPA. Fifty-four patients had α-thal, 75 β-thal, and 12 patients were complex cases, we observed 13 α- and 18 β-thal alleles in 43 genotypes, -α/αα and β/β were the most frequent. Four α-thal deletions (- included and , whereas (αα) involved MCS-R), a hereditary persistence of fetal hemoglobin-2 like (HPFH-2 like) deletion and six alleles not previously reported in Mexicans (αα, -α, αα, β, β and β) were identified. The observed alleles denote the high heterogeneity and multiple origin admixture of Mexican population. Hematological data are consistent with genotypes, variability in simple carriers, from asymptomatic forms to mild or moderate anemia, was ascertained. We emphasize the importance to consider hematological parameters to establish adequate molecular screening strategies.
Topics: Alleles; Cohort Studies; Female; Fetal Hemoglobin; Genotype; Glycated Hemoglobin; Hemoglobin A2; Hemoglobins; Heterozygote; Humans; Male; Mexico; Mutation; alpha-Thalassemia; beta-Globins; beta-Thalassemia
PubMed: 33734896
DOI: 10.1089/gtmb.2020.0276 -
BMC Medical Genetics Jan 2020Thalassemia is a group of inherited hemoglobic disorders resulting from defects in the synthesis of one or more of the hemoglobin chains, which is one of the most...
BACKGROUND
Thalassemia is a group of inherited hemoglobic disorders resulting from defects in the synthesis of one or more of the hemoglobin chains, which is one of the most prevalent inherited disorders in southern China. Only few studies reported the molecular characterization of α- and β-Thalassemia in Hubei Province in the central of China.
METHODS
A total of 4889 clinically suspected cases of thalassemia were analyzed by Gap-PCR, PCR-based reverse dot blot (RDB).
RESULTS
1706 (33.8%) subjects harbored thalassemia mutations, including 539 (11.0%) subjects with α-thalassemia, 1140 (23.3%) subjects with β-thalassemia mutations, and 25 (0.51%) subjects with both α- and β-thalassemia mutations. Seven genotypes of α-thalassemia mutations and 29 genotypes of β-thalassemia mutations were characterized. --/αα (66.05%), -α/αα (24.12%), and -α/αα (3.71%) accounted for 93.88% of the α-thalassemia mutations. βIVS-II-654/βN, βCD41-42/βN, βCD17/βN, βCD27-28/βN, βCD71-72/βN, β - 28/βN, β - 29/βN, βCD43/βN, βE/βN, accounting for 96.40% of all β-thalassemia genotypes. Furthermore, mean corpuscular volume (MCV) and mean corpuscular Hb (MCH) were sensitive markers for both β-thalassemia and α-thalassemia with --/αα, but not -α/αα and -α/αα.
CONCLUSIONS
Our data indicated great heterogeneity and extensive spectrum of thalassemias in Hubei province of China.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Child; Child, Preschool; China; Female; Genetic Heterogeneity; Genetics, Population; Genotype; Hemoglobins; Humans; Infant; Male; Middle Aged; Mutation; Young Adult; alpha-Thalassemia; beta-Thalassemia
PubMed: 31906886
DOI: 10.1186/s12881-019-0925-5 -
JPMA. the Journal of the Pakistan... Jan 2021To evaluate the frequency of alpha thalassemia and detect mutations in the alpha genes in individuals undergoing premarital screening.
OBJECTIVE
To evaluate the frequency of alpha thalassemia and detect mutations in the alpha genes in individuals undergoing premarital screening.
METHODS
The cross-sectional study was conducted at King Fahad Central Hospital, Jazan, Saudi Arabia, from January 2018 to May 2019, and comprised blood samples of individuals visiting the premarital screening clinic. The samples were analyzed for complete blood counts and haemoglobin electrophoresis. Molecular analysis of samples suspected for alpha thalassemia was done using alpha-globin StripAssay kit. Data was anlaysed using SPSS 20.
RESULTS
Of the 3,970 samples analysed, 1,859(46.83%) were from males and 2,111(53.17%) from females. The overall frequency of suspected alpha thalassemia was 4.43% based upon haematological parameters including complete blood count and haemoglobin electrophoresis. Overall, 80 suspected samples were selected for genetic analyses, and, of them, 76 (95%) were positive for deletional and non-deletional mutations of alpha-globin genes, while 4 (5%) were negative for any of the 21 mutations tested.
CONCLUSIONS
Alpha thalassemia was found to be highly prevalent in the study area.
Topics: Cross-Sectional Studies; Female; Genotype; Humans; Male; Saudi Arabia; alpha-Globins; alpha-Thalassemia
PubMed: 33484530
DOI: 10.47391/JPMA.864 -
Hemoglobin Jan 2022Acknowledging and understanding the extent of thalassemia and hemoglobinopathy issues in a country is crucial for the benefit of implementing a national preventive and... (Review)
Review
Acknowledging and understanding the extent of thalassemia and hemoglobinopathy issues in a country is crucial for the benefit of implementing a national preventive and control program to reduce its prevalence. In order to obtain reliable prevalence data, the gene frequencies of the thalassemias and other hemoglobinopathies should be investigated. Molecular studies on thalassemia have yet to be done for Brunei's population. It was estimated that carriers of thalassemia or hemoglobinopathies in Brunei is approximately 5.0% or less of the overall population. There are about 200 current cases of thalassemia and other hemoglobinopathies including adults and children reported across all four districts of Brunei. Blood parameter analysis, microscopy, hemoglobin (Hb) electrophoresis and high performance liquid chromatography (HPLC) are the most common methods of investigation in aiding diagnosis in the hospital laboratory. Genotyping analysis conducted in an overseas laboratory has been employed to confirm some diagnosis. Compiled data from 2009-2017 at the Hematology Laboratory of the Raja Isteri Pengiran Anak Saleha Hospital, Jalan Putera Al-Muhtadee Billah, Bandar Seri Begawan, Brunei Darussalam, showed that the most reported diagnoses are α-thalassemia (α-thal) trait, β-thalassemia (β-thal) trait, heterozygous Hb E (: c.79G>A)/β-thal, β-thal major (β-TM) and β-thal intermedia (β-TI). The data reported indicate the importance of establishing a thalassemia registry with relevant data on patients and patient outcomes as a tool for monitoring and improving patient care.
Topics: Adult; Brunei; Child; Hemoglobinopathies; Heterozygote; Humans; alpha-Thalassemia; beta-Thalassemia
PubMed: 35950589
DOI: 10.1080/03630269.2021.2008959 -
American Journal of Hematology Sep 2023This systematic literature review assessed the global prevalence and birth prevalence of clinically significant forms of alpha- and beta-thalassemia. Embase, MEDLINE,...
This systematic literature review assessed the global prevalence and birth prevalence of clinically significant forms of alpha- and beta-thalassemia. Embase, MEDLINE, and the Cochrane Library were searched for observational studies published January 1, 2000, to September 21, 2021. Of 2093 unique records identified, 69 studies reported across 70 publications met eligibility criteria, including 6 records identified from bibliography searches. Thalassemia prevalence estimates varied across countries and even within countries. Across 23 population-based studies reporting clinically significant alpha-thalassemia (e.g., hemoglobin H disease and hemoglobin Bart's hydrops fetalis) and/or beta-thalassemia (beta-thalassemia intermedia, major, and/or hemoglobin E/beta-thalassemia), prevalence estimates per 100 000 people ranged from 0.2 in Spain (over 2014-2017) to 27.2 in Greece (2010-2015) for combined beta- plus alpha-thalassemia; from 0.03 in Spain (2014-2017) to 4.5 in Malaysia (2007-2018) for alpha-thalassemia; and from 0.2 in Spain (2014-2017) to 35.7 to 49.6 in Iraq (2003-2018) for beta-thalassemia. Overall, the estimated prevalence of thalassemia followed the predicted pattern of being higher in the Middle East, Asia, and Mediterranean than in Europe or North America. However, population-based prevalence estimates were not found for many countries, and there was heterogeneity in case definitions, diagnostic methodology, type of thalassemia reported, and details on transfusion requirements. Limited population-based birth prevalence data were found. Twenty-seven studies reported thalassemia prevalence from non-population-based samples. Results from such studies likely do not have countrywide generalizability as they tended to be from highly specific groups. To fully understand the global prevalence of thalassemia, up-to-date, population-based epidemiological data are needed for many countries.
Topics: Pregnancy; Female; Humans; alpha-Thalassemia; beta-Thalassemia; Prenatal Diagnosis; Hydrops Fetalis; Asia; Hemoglobins, Abnormal
PubMed: 37357829
DOI: 10.1002/ajh.27006 -
Journal of Clinical Pathology May 2020Thalassemia is one of the most prevalent inherited disorders in south China. However, there still has no comprehensive research on molecular characterisation of...
AIMS
Thalassemia is one of the most prevalent inherited disorders in south China. However, there still has no comprehensive research on molecular characterisation of α-thalassemia and β-thalassemia in the Quanzhou region of Fujian province, a city with high incidence of thalassemia in Southeast China.
METHODS
A total of 11 668 cases were collected in Quanzhou region from January 2013 to June 2019. The deletions of α-thalassemia were detected by Gap-PCR, α-thalassemia and β-thalassemia mutations were detected by DNA reverse dot blot hybridisation. Rare thalassemia gene testing and DNA sequencing were performed to detect rare and novel thalassemia mutation for suspected rare thalassemia carriers.
RESULTS
Among 11 668 subjects, 4796 (41.10%) subjects were diagnosed with thalassemia. 3298 (28.27%) subjects were α-thalassemia carriers, 26 types of α-thalassemia mutations were identified, with the common α-thalassemia genotypes being --/αα (71.47%), -α/αα (17.13%) and -α/αα (3.49%). 1407 (12.06%) subjects were β-thalassemia carriers, 18 types of β-thalassemia mutations were identified. The common five genotypes of β-thalassemia were β/β (36.53%), β/β (30.28%), β/β (17.13%), β/β (5.12%) and β/β (4.62%). Additionally, 91 (0.78%) subjects with composite α-thalassemia and β-thalassemia were identified. Furthermore, 9 α-thalassemia and β-thalassemia gene mutations (CAP +40-43 (-AAAC), IVS-I-1 (G>T), IVS-I-5 (G>C), SEA-HPFH, CD53 (-T), CD37 (A>G), -90 (C>T), CD3 (T>C), -α) were identified for the first time in the region. Among them, CD53 (-T), CD37 (A>G) and -90 (C>T) mutations were identified for the first time in Fujian province. Moreover, CD3 (T>C), -α mutations were first identified in Chinese individual.
CONCLUSIONS
Quanzhou region of South China has high incidence of thalassemia mutations. In this study, several cases of rare thalassemia mutations have been identified, providing reference for clinical consultation. The completion of this study is of great significance to strengthen the prevention and control of thalassaemia in the Quanzhou region.
Topics: Adolescent; Adult; China; Female; Genetic Markers; Genotype; Humans; Male; Middle Aged; Mutation; Prevalence; Sequence Analysis, DNA; Young Adult; alpha-Thalassemia; beta-Thalassemia
PubMed: 31653757
DOI: 10.1136/jclinpath-2019-206179 -
MMWR. Morbidity and Mortality Weekly... Sep 2020Alpha-thalassemia comprises a group of inherited disorders in which alpha-hemoglobin chain production is reduced. Depending on the genotype, alpha-thalassemia results in...
Alpha-thalassemia comprises a group of inherited disorders in which alpha-hemoglobin chain production is reduced. Depending on the genotype, alpha-thalassemia results in moderate to profound anemia, hemolysis, growth delays, splenomegaly, and increased risk for thromboembolic events; certain patients might require chronic transfusions. Although alpha-thalassemia is not a core condition of the United States Recommended Uniform Screening Panel* for state newborn screening programs, methodologies used by some newborn screening programs to detect sickle cell disease, which is a core panel condition, also detect a quantitative marker of alpha-thalassemia, hemoglobin (Hb) Bart's, an abnormal type of hemoglobin. The percentage of Hb Bart's detected correlates with alpha-thalassemia severity. The Association of Public Health Laboratories' Hemoglobinopathy Workgroup conducted a survey of state newborn screening programs' alpha-thalassemia screening methodologies and reporting and follow-up practices. Survey findings indicated that 41 of 44 responding programs (93%) report some form of alpha-thalassemia results and 57% used a two-method screening protocol. However, the percentage of Hb Bart's used for thalassemia classification, the types of alpha-thalassemia reported, and the recipients of this information varied widely. These survey findings highlight the opportunity for newborn screening programs to revisit their policies as they reevaluate their practices in light of the recently released guideline from the Clinical and Laboratory Standards Institute (CLSI) on Newborn Screening for Hemoglobinopathies (1). Although deferring to local programs for policies, the report used a cutoff of 25% Hb Bart's in its decision tree, a value many programs do not use. Standardization of screening and reporting might lead to more timely diagnoses and health care services and improved outcomes for persons with a clinically significant alpha-thalassemia.
Topics: Female; Health Care Surveys; Humans; Infant, Newborn; Male; Neonatal Screening; United States; alpha-Thalassemia
PubMed: 32915167
DOI: 10.15585/mmwr.mm6936a7