The UK National External Quality Assessment Scheme for Heritable Bleeding Disorders

Perry, David J.; Cumming, Tony; Goodeve, Anne; Hill, Marian; Jennings, Ian; Kitchen, S.; Walker, Isobel

doi:10.1055/s-0034-1365843

Cited by 7 publications

(5 citation statements)

References 18 publications

(15 reference statements)

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“…Two points are awarded for each of the survey areas, and participants must gain at least one point in each area to pass the exercise. The scheme has seen rapid improvement in report format and essential inclusions from new scheme participants .…”

Section: External Quality Assessment (Eqa)mentioning

confidence: 99%

Hemophilia B: molecular pathogenesis and mutation analysis

Goodeve

2015

Journal of Thrombosis and Haemostasis

103

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SummaryHemophilia B is an X‐chromosome‐linked inherited bleeding disorder primarily affecting males, but those carrier females with reduced factor IX activity (FIX:C) levels may also experience some bleeding. Genetic analysis has been undertaken for hemophilia B since the mid‐1980s, through linkage analysis to track inheritance of an affected allele, and to enable determination of the familial mutation. Mutation analysis using PCR and Sanger sequencing along with dosage analysis for detection of large deletions/duplications enables mutation detection in > 97% of patients with hemophilia B. The risk of the development of inhibitory antibodies, which are reported in ~ 2% of patients with hemophilia B, can be predicted, especially in patients with large deletions, and these individuals are also at risk of anaphylaxis, and nephrotic syndrome if they receive immune tolerance induction. Inhibitors also occur in patients with nonsense mutations, occasionally in patients with small insertions/deletions or splice mutations, and rarely in patients with missense mutations (p.Gln237Lys and p.Gln241His). Hemophilia B results from several different mechanisms, and those associated with hemophilia B Leyden, ribosome readthrough of nonsense mutations and apparently ‘silent’ changes that do not alter amino acid coding are explored. Large databases of genetic variants in healthy individuals and patients with a range of disorders, including hemophilia B, are yielding useful information on sequence variant frequency to help establish possible variant pathogenicity, and a growing range of algorithms are available to help predict pathogenicity for previously unreported variants.

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Section: External Quality Assessment (Eqa)mentioning

confidence: 99%

Hemophilia B: molecular pathogenesis and mutation analysis

Goodeve

2015

Journal of Thrombosis and Haemostasis

103

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“…10 EQA for laboratory genetic investigations is therefore required for those laboratories performing genetic testing for VWD, and has been provided by UK NEQAS BC for over 18 years. 11 We report here findings from recent EQA exercises, as well as from a questionnaire about diagnostic practices employed by centers in the UK NEQAS program performing VWF assays.…”

mentioning

confidence: 99%

External Quality Assessment Data for Investigation of von Willebrand Disease: Focus on Relative Utility of Contemporary Functional von Willebrand Factor Assays. The United Kingdom National External Quality Assessment Scheme (UK NEQAS) Experience

Jennings¹,

Reilly-Stitt²,

Lowe³

et al. 2022

Semin Thromb Hemost

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Von Willebrand disease (VWD) is one of the most common hereditary bleeding disorders. Effective management of patients and their families depends on accurate diagnosis and subtype classification, and quality assurance including participation in proficiency testing programs is essential to ensure the accuracy of the panel of assays required to achieve this diagnosis. We report here findings from recent external quality assessment (EQA) exercises, as well as from a questionnaire about diagnostic practices employed by centers in the United Kingdom National Quality Assessment Scheme (UK NEQAS) performing von Willebrand factor (VWF) assays. Plasma samples from donors with VWD, “normal” donors, the International Society for Thrombosis and Haemostasis Scientific Subcommittee (ISTH SSC) plasma standard, and whole blood samples were sent to participants in the UK NEQAS BC program for VWF investigation. Calibration of lot#5 of the ISTH SSC plasma standard was shown to give improved comparability between the recovered value from an EQA exercise and the assigned potency for VWF activity assays. Diagnostic accuracy and precision amongst UK NEQAS participants was good, with an average 99% of centers reporting the correct interpretation for normal, type 1 and type 2 VWD samples, 100% diagnostic accuracy for centers performing FVIII binding assays, and good agreement amongst centers performing multimeric analysis. Genetic analysis of the VWF gene by specialist centers demonstrated errors in the genotyping process in one center, but also demonstrated failings in the interpretation of results in other centers. Despite evidence of good laboratory accuracy and precision in their assays, a questionnaire identified marked variation in diagnostic criteria employed, underlining the importance of guidelines to support the diagnosis of VWD.

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“…This involves appropriate patient selection as well as pre-and post-test counseling, along with appropriate test selection. 11,12 Interpretation and accurate reporting of test results are also essential, particularly when novel sequence variants are identified 13 and, together with clerical errors, account for an important source of errors in genetic testing. 11 This article aims to review our local experience with HB genetic testing and describe outcomes of pre-test selection and the spectrum of variants identified in a sample of individuals referred to our hemophilia reference laboratory.…”

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confidence: 99%

Factor IX Gene (F9) Genotyping Trends and Spectrum of Mutations Identified: A Reference Laboratory Experience

Botero

Coon

Majerus

et al. 2017

Semin Thromb Hemost

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In hemophilia B (HB), factor IX gene ( genotyping is used for molecular confirmation of affected individuals, for carrier testing, to facilitate the identification of those at risk for anaphylaxis/inhibitors (associated with large deletions), and to assist in assigning disease severity. Owing to test costs, optimal test utilization involves pre/post-test counseling and appropriate patient and test selection (e.g., mutation screening [MS] vs. known mutation [KM] testing). This article aims to review the trends and outcomes of -genotyping orders and describe the spectrum of variants identified in a sample of individuals in our reference laboratory. We performed a retrospective review of consecutive orders submitted to the Special Coagulation DNA Diagnostic Laboratory, Mayo Clinic, between 2012 and 2015. A total of 133 orders (38%) were identified for men: 118 (88%) wereMS and 15 (12%) were KM. Thirteen orders (10%) were cancelled. A total of 209 orders were identified for women: 178 (85%) wereMS and 31 (15%) were KM. Thirty-seven orders (18%) were cancelled and 30% of the tests performed yielded negative results. A total of 164 samples (47%) were received without clinical information. Seventeen previously unreported variants were identified. genotyping provides useful information for HB management; however, 18% of our orders were cancelled and almost half were received without relevant clinical information, thus reaffirming the need for ongoing scrutiny of submitted orders. Optimal patient and test selection is important as is the accurate interpretation of variants identified. Most of the pathogenic variants identified were point mutations, with very few large deletions, consistent with the literature.

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The UK National External Quality Assessment Scheme for Heritable Bleeding Disorders

Cited by 7 publications

References 18 publications

Hemophilia B: molecular pathogenesis and mutation analysis

Hemophilia B: molecular pathogenesis and mutation analysis

External Quality Assessment Data for Investigation of von Willebrand Disease: Focus on Relative Utility of Contemporary Functional von Willebrand Factor Assays. The United Kingdom National External Quality Assessment Scheme (UK NEQAS) Experience

Factor IX Gene (F9) Genotyping Trends and Spectrum of Mutations Identified: A Reference Laboratory Experience

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