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

Cheryl Stopford, Oliver W. Quarrell, Olivia Handley, Kirsty O'Donovan, Christine Dumoulin, Maria Ramos-Arroyo, Ida Biunno, Peter Bauer, Margaret Kline, G. Bernhard Landwehrmeyer, David Craufurd

    Research output: Contribution to journalArticlepeer-review

    Abstract

    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. © 2012 Macmillan Publishers Limited All rights reserved.
    Original languageEnglish
    Pages (from-to)20-26
    Number of pages6
    JournalEuropean Journal of Human Genetics
    Volume20
    Issue number1
    DOIs
    Publication statusPublished - Jan 2012

    Keywords

    • CAG repeat length
    • Huntington's disease
    • standard reference materials

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