TY - JOUR
T1 - Discrepancies in reporting the CAG repeat lengths for Huntington’s disease
AU - the European Huntington’s Disease Network
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 - Barth, Katrin
AU - Correia Guedes, Leonor
AU - Finisterra, Ana Maria
AU - Garde, Monica Bascunãna
AU - Bos, Reineke
AU - Ecker, Daniel
AU - Held, Christine
AU - Koppers, Kerstin
AU - Laurà, Mathilde
AU - Descals, Asunción Martínez
AU - McLean, Tim
AU - Mestre, Tiago
AU - Minster, Sara
AU - Monza, Daniela
AU - Townhill, Jenny
AU - Orth, Michael
AU - Padieu, Helene
AU - Paterski, Laurent
AU - Peppa, Nadia
AU - Koivisto, Susana Pro
AU - Rialland, Amandine
AU - Røren, Ninni
AU - Šašinková, Pavla
AU - Trigo Cubillo, Patricia
AU - van Walsem, Marlene R.
AU - Witjes-Ané, Marie Noëlle
AU - Yudina, Elizaveta
AU - Zielonka, Daniel
AU - Zielonka, Eugeniusz
AU - Zinzi, Paola
AU - Bachoud-Lévi, A. C.
AU - Bentivoglio, Anna Rita
AU - Bonelli, R.
AU - Burgunder, Jean Marc
AU - Dunnett, S. B.
AU - Ferreira, J. J.
AU - Handley, O. J.
AU - Heiberg, Arvid
AU - Illmann, T.
AU - Levey, J.
AU - Nielsen, Jørgen E.
N1 - Publisher Copyright:
© 2012 Macmillan Publishers Limited. All rights reserved.
PY - 2012/1
Y1 - 2012/1
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 - CAG repeat length
KW - Huntington’s disease
KW - Standard reference materials
UR - http://www.scopus.com/inward/record.url?scp=83255194123&partnerID=8YFLogxK
U2 - 10.1038/ejhg.2011.136
DO - 10.1038/ejhg.2011.136
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C2 - 21811303
AN - SCOPUS:83255194123
SN - 1018-4813
VL - 20
SP - 20
EP - 26
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 1
ER -