Ten Years of Routine<b>α</b>- and<b>β</b>-Globin Gene Sequencing in UK Hemoglobinopathy Referrals Reveals 60 Novel Mutations

Henderson, Shirley; Timbs, Adele; McCarthy, Janice; Gallienne, Alice; Proven, Melanie; Rugless, Michelle; Lopez, Herminio; Eglinton, Jennifer; Dziedzic, Dariusz; Beardsall, Matthew; Khalil, Mohamed S; Old, John

doi:10.3109/03630269.2015.1113990

Cited by 40 publications

(29 citation statements)

References 12 publications

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“…With the advent of NGS techniques in recent years, NGS emerged as a popular tool in prenatal screening . So far, many recent investigations confirmed the advantage of NGS in screening thalassemia carriers and detecting novel and complex variations . An investigation of prevalence and genetic background of thalassemia in Baise Region found 24 common variations and 4 rare novel variations .…”

Section: Discussionmentioning

confidence: 99%

Next‐generation sequencing improves molecular epidemiological characterization of thalassemia in Chenzhou Region, P.R. China

Zhang

et al. 2019

Clinical Laboratory Analysis

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ObjectivesThalassemia is a highly prevalent monogenic inherited disease in southern China. It is important to collect epidemiological data comprehensively for proper prevention and treatment.MethodsIn this study, blood samples collected from 15 807 residents of Chenzhou were primarily screened by hematological tests. A total of 3973 samples of suspected thalassemia carriers were further characterized by combined next‐generation sequencing (NGS) and Gap‐PCR.ResultsIn total, 1704 subjects were diagnosed as thalassemia carriers with a total prevalence rate of 10.78%, including 943 α‐thalassemia carriers, 708 β‐thalassemia carriers, and 53 composite α and β‐thalassemia carriers. The prevalence rates of α‐thalassemia, β‐thalassemia, and composite α and β‐thalassemia were 5.97%, 4.48%, and 0.34%, respectively. Meanwhile, we characterized 19 α‐thalassemia variations and 21 β‐thalassemia variations in thalassemia carriers. Approximately 2.88% of thalassemia carriers would be missed by traditional genetic analysis. In addition, four novel thalassemia mutations and one novel abnormal hemoglobin mutation were identified.ConclusionsOur data suggest a high prevalence of thalassemia and a diverse spectrum of thalassemia‐associated variations in Chenzhou. Also, combined NGS and Gap‐PCR is an effective thalassemia screening method. Our findings might be helpful for prevention and treatment of thalassemia in this region.

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Section: Discussionmentioning

confidence: 99%

Next‐generation sequencing improves molecular epidemiological characterization of thalassemia in Chenzhou Region, P.R. China

Zhang

et al. 2019

Clinical Laboratory Analysis

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“…This has resulted in the discovery of 60 novel thalassemia and abnormal haemoglobin mutations over a period of ten years. These consisted of 11 novel β-chain variants, 15 α-chain variants, 19 β-thalassaemia mutations (Table 1) and 15 non-deletional α + -thalassaemia mutations (Table 2) [7]. The discovery rate of novel mutations each year appears to be constant, with 29 found in the first five years and 31 in the second five year period, reflecting a continual influx of new immigrant populations to the UK over the ten year period.…”

Section: Resultsmentioning

confidence: 99%

“…To simplify the diagnostic strategy, it was decided to also amplify the α-globin genes routinely on all referred samples in addition to routinely screening for deletion mutations by gap-PCR or MLPA. Since the change in diagnostic strategy, approximately 12,000 DNA samples underwent PCR to selectively amplify the β-, α1-and α2-globin genes [7]. The PCR products were cleaned up and quantified by gel electrophoresis before being subjected to cycle sequencing.…”

Section: Methodsmentioning

confidence: 99%

New Challenges in Diagnosis of Haemoglobinopathies: Migration of Populations

Old¹,

Timbs²,

McCarthy³

et al. 2018

Thalassemia Reports

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The current influx of economic migrants and asylum seekers from countries with a high prevalence of haemoglobinopathies creates new challenges for health care systems and diagnostic laboratories. The migration of carriers introduces new and novel haemoglobinopathy mutations to the diagnostic repertoire of a laboratory, often creating new pressures to improve and update the carrier screening technology and diagnostic scope. For antenatal screening programmes, the marriage of partners from different ethnic groups can lead to the risk of compound heterozygote children being born novel mutation combinations, creating problems in the provision of accurate advice regarding the expected phenotype of the thalassaemia or haemoglobinopathy disorder. In the UK, the impact of immigration required the National Haemoglobinopathy Reference laboratory to change the strategy and techniques used for the molecular diagnosis of thalassaemia and the haemoglobinopathies. In 2005, due to the increasingly large range of β-thalassaemia mutations that needed to be diagnosed, the laboratory switched from a three-step screening procedure using ARMS-PCR to a simpler but more expensive one-step strategy of DNA sequencing of the beta and alpha globin genes for all referrals. After ten years of employing this strategy, a further 57 novel thalassaemia and haemoglobionpopthy alleles were discovered (11 new β-chain variants, 15 α-chain variants, 19 β-thalassaemia mutations and 12 α + -thalassaemia mutations), increasing further the extremely heterogeneous spectrum of globin gene mutations in the UK population.

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“…Eleven of these variants may have been missed if DNA sequencing was not done as they ran with hemoglobin A on HPLC. The immigrant population in the UK was responsible for the large number of β thalassemic alleles seen due to the racial heterogeneity …”

Section: Discussionmentioning

confidence: 99%

“…The immigrant population in the UK was responsible for the large number of β thalassemic alleles seen due to the racial heterogeneity. 59 In a 20-year retrospective analysis of the spectrum of α, β, and δ gene mutations in four districts in Cyprus, which has the highest prevalence of thalassemia globally, 13824 carriers and all known 592 β thalassemia patients and 595 Hb H disease patients were analyzed. Notable differences were found in the frequencies of different mutations between the four districts in this small island, and several mutations were being reported for the first time in this population.…”

Section: Many Of the Uncommon β Chain Hemoglobin Variants Likementioning

confidence: 99%

The phenotypic and molecular diversity of hemoglobinopathies in India: A review of 15 years at a referral center

Nadkarni

Gorakshakar

Sawant

et al. 2018

Int J Lab Hematology

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Introduction The hemoglobinopathies pose a significant health burden in India. Apart from the β thalassemias and sickle cell disorders, α thalassemias and structural hemoglobin variants are also common. Here we have reviewed the phenotypic and molecular diversity of hemoglobinopathies encountered at a referral center in western India over a period of 15 years. Materials and Methods Screening for hemoglobinopathies was done using HPLC and cellulose acetate electrophoresis. Molecular characterization was done using Covalent Reverse Dot Blot Hybridization (CRDB), Amplification Refractory Mutation System (ARMS), GAP PCR and direct DNA sequencing. Results The study includes 31 075 individuals who were referred for diagnosis of hemoglobinopathies and prenatal diagnosis. Of these 14 423 individuals showed various hemoglobin abnormalities. Beta genotyping in 5615 individuals showed the presence of 49 β thalassemia mutations. 143 β thalassemia heterozygotes had normal or borderline HbA2 levels. We identified three δ gene mutations (HbA2 Pellendri, HbA2 St.George, HbA2 Saurashtra) in β thalassemia heterozygotes leading to normal HbA2 levels. The commonest defects among the raised Hb F determinants were Gγ(Αγδβ)0 Indian inversion and the HPFH‐3 Indian deletion. A total of 312 individuals showed the presence of α thalassemia, of which 12.0% had a single α gene deletion (−α/αα). HbH disease was identified in 29 cases with 10 different genotypes. Alpha globin gene triplication was seen in 2.1% of β thalassemia heterozygotes with a thalassemia intermedia phenotype. Seven unusual α chain variants and eight uncommon β chain variants were identified. Conclusion The repertoire of molecular defects seen in the different globin genes will be valuable for management and control of these disorders both in India as well as in other countries where there is a huge influx of migrant populations from India.

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Ten Years of Routineα- andβ-Globin Gene Sequencing in UK Hemoglobinopathy Referrals Reveals 60 Novel Mutations

Cited by 40 publications

References 12 publications

Next‐generation sequencing improves molecular epidemiological characterization of thalassemia in Chenzhou Region, P.R. China

Next‐generation sequencing improves molecular epidemiological characterization of thalassemia in Chenzhou Region, P.R. China

New Challenges in Diagnosis of Haemoglobinopathies: Migration of Populations

The phenotypic and molecular diversity of hemoglobinopathies in India: A review of 15 years at a referral center

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