The UK National External Quality Assessment Scheme for Heritable Bleeding Disorders

Abstract

Molecular genetic analysis of families with hemophilia and other heritable bleeding disorders is a frequently requested laboratory investigation. In the United Kingdom, laboratories undertaking genetic testing must participate in a recognized external quality assessment scheme for formal accreditation. The UK National External Quality Assessment Scheme (UK NEQAS) for heritable bleeding disorders was established in its current format in 2003, and currently has 27 registered participants in the United Kingdom, the European Union (EU), and the non-EU countries. Two exercises per annum are circulated to participants comprising either whole blood or DNA isolated from cell lines, and laboratories are allowed 6 weeks to analyze the samples and generate a report. Reports are assessed by a panel comprising clinicians and scientists with expertise in this area. Samples to date have involved analysis of the F8 gene (10 exercises), the F9 gene (4 exercises), and the VWF gene (3 exercises) and have comprised a wide spectrum of mutations representing the routine workload encountered in the molecular genetics laboratory. The majority of laboratories in each exercise passed, but a small number did not and reasons for failing included clerical errors, genotyping inaccuracies, and a failure to correctly interpret data. Overall we have seen an improvement in quality of reports submitted for assessment, with a more concise format that will be of value to referring clinicians and counsellors. Informal feedback from participants has been very positive.

Keywords

quality assurance - hemophilia - molecular genetics - mutational analysis

• References

• 1 Schwarz J, Astermark J, Menius ED , et al; Hemophilia Inhibitor Genetics Study Combined Cohort. F8 haplotype and inhibitor risk: results from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort. Haemophilia 2013; 19 (1) 113-118
• 2 Gouw SC, van den Berg HM, Oldenburg J , et al. F8 gene mutation type and inhibitor development in patients with severe hemophilia A: systematic review and meta-analysis. Blood 2012; 119 (12) 2922-2934
• 3 Tripodi A, Peyvandi F, Chantarangkul V, Menegatti M, Mannucci PM. Relatively poor performance of clinical laboratories for DNA analyses in the detection of two thrombophilic mutations—a cause for concern. Thromb Haemost 2002; 88 (4) 690-691
• 4 Preston FE, Kitchen S, Jennings I, Woods TA. A UK National External Quality Assessment scheme (UK Neqas) for molecular genetic testing for the diagnosis of familial thrombophilia. Thromb Haemost 1999; 82 (5) 1556-1557
• 5 Mueller CR, Kristoffersson U, Stoppa-Lyonnet D. External quality assessment for mutation detection in the BRCA1 and BRCA2 genes: EMQN's experience of 3 years. Ann Oncol 2004; 15 (Suppl. 01) I14-I17
• 6 Hertzberg M, Neville S, Favaloro E, McDonald D. External quality assurance of DNA testing for thrombophilia mutations. Am J Clin Pathol 2005; 123 (2) 189-193
• 7 Dequeker E, Cassiman JJ. Genetic testing and quality control in diagnostic laboratories. Nat Genet 2000; 25 (3) 259-260
• 8 EQA Schemes. http://www.emqn.org/emqn/Schemes . Accessed January 30, 2014
• 9 Keeney S, Mitchell M, Goodeve A ; UK Haemophilia Center Doctors' Organization Haemophilia Genetics Laboratory Network. The molecular analysis of haemophilia A: a guideline from the UK haemophilia centre doctors' organization haemophilia genetics laboratory network. Haemophilia 2005; 11 (4) 387-397
• 10 Keeney S, Bowen D, Cumming A, Enayat S, Goodeve A, Hill M ; UK Haemophilia Centre Doctors' Organisation (UKHCDO). The molecular analysis of von Willebrand disease: a guideline from the UK Haemophilia Centre Doctors' Organisation Haemophilia Genetics Laboratory Network. Haemophilia 2008; 14 (5) 1099-1111
• 11 Mitchell M, Keeney S, Goodeve A ; UK Haemophilia Centre Doctors' Organization Haemophilia Genetics Laboratory Network. The molecular analysis of haemophilia B: a guideline from the UK haemophilia centre doctors' organization haemophilia genetics laboratory network. Haemophilia 2005; 11 (4) 398-404
• 12 Kernoff PB, Lee CA, Karayiannis P, Thomas HC. High risk of non-A non-B hepatitis after a first exposure to volunteer or commercial clotting factor concentrates: effects of prophylactic immune serum globulin. Br J Haematol 1985; 60 (3) 469-479
• 13 Darby SC, Ewart DW, Giangrande PL, Dolin PJ, Spooner RJ, Rizza CR. Mortality before and after HIV infection in the complete UK population of haemophiliacs. UK Haemophilia Centre Directors' Organisation. Nature 1995; 377 (6544) 79-82
• 14 Perry DJ, Goodeve A, Hill M, Jennings I, Kitchen S, Walker I ; UK NEQAS for Blood Coagulation. The UK National External Quality Assessment Scheme (UK NEQAS) for molecular genetic testing in haemophilia. Thromb Haemost 2006; 96 (5) 597-601
• 15 Antonarakis SE, Rossiter JP, Young M , et al. Factor VIII gene inversions in severe hemophilia A: results of an international consortium study. Blood 1995; 86 (6) 2206-2212
• 16 Liu Q, Nozari G, Sommer SS. Single-tube polymerase chain reaction for rapid diagnosis of the inversion hotspot of mutation in hemophilia A. Blood 1998; 92 (4) 1458-1459
• 17 Rossetti LC, Radic CP, Larripa IB, De Brasi CD. Genotyping the hemophilia inversion hotspot by use of inverse PCR. Clin Chem 2005; 51 (7) 1154-1158
• 18 Bagnall RD, Waseem N, Green PM, Giannelli F. Recurrent inversion breaking intron 1 of the factor VIII gene is a frequent cause of severe hemophilia A. Blood 2002; 99 (1) 168-174
• 19 Best Practice Guidelines. http://www.cmgs.org/BPGs/Best_Practice_Guidelines.htm . Accessed January 30, 2014
• 20 Ludlam CA, Pasi KJ, Bolton-Maggs P , et al; UK Haemophilia Centre Doctors' Organisation. A framework for genetic service provision for haemophilia and other inherited bleeding disorders. Haemophilia 2005; 11 (2) 145-163
• 21 den Dunnen J. Nomenclature for the description of sequence variants. Human Genome Variation Society Web site. http://www.hgvs.org/mutnomen/ . Accessed January 30, 2014