TY - JOUR

T1 - Discrepancies in reporting the CAG repeat lengths for Huntington's disease

AU - Quarrell, Oliver W

AU - Handley, Olivia

AU - O'Donovan, Kirsty

AU - Dumoulin, Christine

AU - Ramos-Arroyo, Maria

AU - Biunno, Ida

AU - Bauer, Peter

AU - Kline, Margaret

AU - Landwehrmeyer, G Bernhard

AU - Hjermind, Lena Elisabeth

AU - Hasholt, Lis Frydenreich

AU - Nørremølle, Anne

AU - Nielsen, Jørgen Erik

AU - European Huntington’s Disease Network

PY - 2011/8

Y1 - 2011/8

N2 - Huntington's disease results from a CAG repeat expansion within the Huntingtin gene; this is measured routinely in diagnostic laboratories. The European Huntington's Disease Network REGISTRY project centrally measures CAG repeat lengths on fresh samples; these were compared with the original results from 121 laboratories across 15 countries. We report on 1326 duplicate results; a discrepancy in reporting the upper allele occurred in 51% of cases, this reduced to 13.3% and 9.7% when we applied acceptable measurement errors proposed by the American College of Medical Genetics and the Draft European Best Practice Guidelines, respectively. Duplicate results were available for 1250 lower alleles; discrepancies occurred in 40% of cases. Clinically significant discrepancies occurred in 4.0% of cases with a potential unexplained misdiagnosis rate of 0.3%. There was considerable variation in the discrepancy rate among 10 of the countries participating in this study. Out of 1326 samples, 348 were re-analysed by an accredited diagnostic laboratory, based in Germany, with concordance rates of 93% and 94% for the upper and lower alleles, respectively. This became 100% if the acceptable measurement errors were applied. The central laboratory correctly reported allele sizes for six standard reference samples, blind to the known result. Our study differs from external quality assessment (EQA) schemes in that these are duplicate results obtained from a large sample of patients across the whole diagnostic range. We strongly recommend that laboratories state an error rate for their measurement on the report, participate in EQA schemes and use reference materials regularly to adjust their own internal standards.

AB - Huntington's disease results from a CAG repeat expansion within the Huntingtin gene; this is measured routinely in diagnostic laboratories. The European Huntington's Disease Network REGISTRY project centrally measures CAG repeat lengths on fresh samples; these were compared with the original results from 121 laboratories across 15 countries. We report on 1326 duplicate results; a discrepancy in reporting the upper allele occurred in 51% of cases, this reduced to 13.3% and 9.7% when we applied acceptable measurement errors proposed by the American College of Medical Genetics and the Draft European Best Practice Guidelines, respectively. Duplicate results were available for 1250 lower alleles; discrepancies occurred in 40% of cases. Clinically significant discrepancies occurred in 4.0% of cases with a potential unexplained misdiagnosis rate of 0.3%. There was considerable variation in the discrepancy rate among 10 of the countries participating in this study. Out of 1326 samples, 348 were re-analysed by an accredited diagnostic laboratory, based in Germany, with concordance rates of 93% and 94% for the upper and lower alleles, respectively. This became 100% if the acceptable measurement errors were applied. The central laboratory correctly reported allele sizes for six standard reference samples, blind to the known result. Our study differs from external quality assessment (EQA) schemes in that these are duplicate results obtained from a large sample of patients across the whole diagnostic range. We strongly recommend that laboratories state an error rate for their measurement on the report, participate in EQA schemes and use reference materials regularly to adjust their own internal standards.

KW - Alleles

KW - Diagnostic Errors

KW - Genetic Testing

KW - Guidelines as Topic

KW - Humans

KW - Huntington Disease

KW - International Cooperation

KW - Mutation

KW - Nerve Tissue Proteins

KW - Nuclear Proteins

KW - Reference Standards

KW - Reproducibility of Results

KW - Sensitivity and Specificity

KW - Trinucleotide Repeats

U2 - 10.1038/ejhg.2011.136

DO - 10.1038/ejhg.2011.136

M3 - Journal article

C2 - 21811303

VL - 20

SP - 20

EP - 26

JO - European Journal of Human Genetics

JF - European Journal of Human Genetics

SN - 1018-4813

IS - 1

ER -