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

Oliver William Quarrell (1) , Olivia Handley (1) , Kirsty O'Donovan (1) , Christine Dumoulin (1) , Maria Ramos-Arroyo (1) , Ida Biunno (1) , Peter Bauer (1) , Margaret Kline (1) , G. Bernhard Landwehrmeyer (1)

1 Department of Clinical Genetics,

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%. Clinically significant discrepancies occurred in 4.0% of cases with a potential unexplained mis-diagnosis rate of 0.3%. There was considerable variation in the discrepancy rate among 10 of the countries participating in this study. 348/1326 DNA samples 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 6 standard reference samples, blind to the known result. Our study differs from external quality assessment 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 external quality assessment schemes and use reference materials regularly to adjust their own internal standards.

Mots clés: Huntington's disease; CAG repeat length; standard reference materials

Domaines: Génétique

Oliver William Quarrell, Olivia Handley, Kirsty O'Donovan, Christine Dumoulin, Maria Ramos-Arroyo, et al.. Discrepancies in reporting the CAG repeat lengths for Huntington's disease. European Journal of Human Genetics, 2011, ⟨10.1038/ejhg.2011.136⟩. ⟨hal-00665875⟩