title: Highly accurate molecular genetic testing for HFE hereditary hemochromatosis: results from 10 years of blinded proficiency surveys by the College of American Pathologists.
abstract: The College of American Pathologists offers blinded proficiency testing (PT) for laboratories performing HFE genetic tests for hereditary hemochromatosis (common C282Y and H63D variants). This study used 10 years of PT data to determine laboratory performance for HFE analytical genotyping and clinical interpretation.
  
  
  
  Laboratories were graded for accuracy of genotype determination (six possible C282Y/H63D genotypes) and clinical interpretation regarding whether the genotype was likely to have contributed to iron overload in a hypothetical patient.
  
  
  
  The analytical genotyping error rate was low (0.73%) in 7,663 results (from 257 unique laboratories). Genotyping errors were significantly higher in C282Y heterozygous, H63D homozygous, and C282Y homozygous samples, in non-American laboratories, and in laboratories with lower testing volume. Analytical sensitivity and specificity were >98.5 and >99.5%. The interpretive error rate (4.3%) was higher than the genotyping error rate, with two problematic genotypes (C282Y heterozygous and H63D homozygous) accounting for 77% of total interpretive errors. There was a time-dependent improvement in the interpretation of the clinical significance of HFE genotypes.
  
  
  
  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.
authors.affiliation: Department of Pathology, Oregon Health and Science University, Portland, Oregon, USA.|Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon, USA.|Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon, USA.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Press
authors.affiliation: Department of Pathology, Oregon Health and Science University, Portland, Oregon, USA.|Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon, USA.
authors.forename: Garrett
authors.identifier: 0000-0002-5732-735X
authors.initials: G
authors.lastname: Eickelberg
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: McDonald
authors.affiliation: College of American Pathologists, Northfield, Illinois, USA.
authors.forename: Jaimie
authors.initials: J
authors.lastname: Halley
authors.affiliation: Department of Biostatistics, College of American Pathologists, Northfield, Illinois, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Long
authors.affiliation: Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA.|The Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Tafe
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.|Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Weck
mesh_terms: D005820:Genetic Testing; D005838:Genotype; D006432:Hemochromatosis / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D000071020:Hemochromatosis Protein / Q000235:genetics*; D006801:Humans; D020125:Mutation, Missense
chemical_list: C103673:HFE protein, human; D000071020:Hemochromatosis Protein