Highly accurate molecular genetic testing for HFE hereditary hemochromatosis: results from 10 years of blinded proficiency surveys by the College of American Pathologists

Abstract

HFE molecular genetic testing, performed by non-US Food and Drug Administration-approved laboratory-developed tests, demonstrated excellent accuracy, sensitivity, and specificity. Clinical interpretations were more heterogeneous, probably owing to the low clinical penetrance of some common HFE genotypes.Genet Med 18 12, 1206-1213.

A panoramic view of the accuracy of molecular genetic testing

“…Overall, there has been excellent performance by clinical laboratories participating in the CAP molecular genetics PT programs, with >95% analytical sensitivity and >99% specificity for all tests analyzed by the CAP/ACMG BMG committee ( Table 1). This compares quite favorably with analytical accuracy parameters for other laboratory analytes (as summarized elsewhere 8 ). This is encouraging because the educational nature of these surveys tends to include particularly challenging genotypes at a much higher frequency than would be expected to be observed in a clinical molecular diagnostic laboratory.…”

“…The paper by Richards et al, "Results From an External Proficiency Testing Program: Eleven Years of Molecular Genetics Testing for Myotonic Dystrophy Type 1, " 1 is the latest in a series of articles in this journal summarizing the performance of laboratories engaged in the College of American Pathologists (CAP) proficiency testing (PT) surveys. [1][2][3][4][5][6][7][8] In each of these articles, approximately 10 years of PT data were analyzed for overall performance by molecular genetics laboratories and for global performance over time; these data were not provided to individual participating laboratories and are not available outside of these publications. It is not feasible to publish all PT survey data at once because there are so many data points to analyze and there are different aspects that are important to address for each clinical disease/test.…”

“…9 The joint CAP/ACMG Biochemical and Molecular Genetics (BMG) committee oversees the CAP PT surveys for molecular genetic testing and has worked to summarize the longitudinal data from the PT surveys for seven of the most commonly tested genetic diseases and for methodsbased PT for Sanger sequencing. [1][2][3][4][5][6][7][8] The data from individual rounds of PT, which are offered two times per year, are not made publicly available by CAP, except to laboratories enrolled in their PT programs.…”

Prevalence of HFE‐related haemochromatosis and secondary causes of hyperferritinaemia and their association with iron overload in 1059 French patients treated by venesection

“…This second explanation was previously given by the College of American Pathologists, who evaluated the performance of 257 laboratories for HFE analytical genotyping and clinical interpretation between 2004 and 2013. The authors argued for further consensus and standardisation in the laboratory reports that go to clinicians 29 . In line with this idea, the European Molecular Genetics Quality Network commissioned clinicians and geneticists to provide recommendations on: (i) criteria for testing, (ii) strategies for testing and (iii) reporting results for the molecular testing of HFE ‐related haemochromatosis, as well as rarer forms of the disease 9 .…”

CAP/ACMG proficiency testing for biochemical genetics laboratories: a summary of performance

“…Despite the nonstandardized nature of laboratory testing, molecular genetic testing quality is very high. 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 Nevertheless, biochemical genetic testing poses unique challenges to the clinical laboratory, including the innate task of assessing multiple analytes in a single test, and the inter- and intrapatient metabolic variability due to genotype, clinical status, or other intrinsic and extrinsic factors. Thus, it is vital that laboratories perform extensive validation and ongoing test monitoring to ensure the highest quality for patient care.…”