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Am J Hum Genet. 2014 Oct 2;95(4):371-82. doi: 10.1016/j.ajhg.2014.09.003.

Ascertainment bias causes false signal of anticipation in genetic prion disease.

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Prion Alliance, Cambridge, MA 02139, USA; Broad Institute, Cambridge, MA 02142, USA; Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address:
National Reference Center for TSE, Georg-August University, 37073 Goettingen, Germany; German Center for Neurodegenerative Disease (DZNE), 37073 Goettingen, Germany.
Australian National Creutzfeldt-Jakob Disease Registry, The University of Melbourne, Parkville, Australia 3010.
National Reference Center for TSE, Georg-August University, 37073 Goettingen, Germany.
MRC Prion Unit, Department of Neurodegenerative Disease, University College London (UCL) Institute of Neurology, and NHS National Prion Clinic, National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Trust, Queen Square, WC1N 3BG London, UK.
Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA 94158, USA.


Anticipation is the phenomenon whereby age of onset in genetic disease decreases in successive generations. Three independent reports have claimed anticipation in Creutzfeldt-Jakob disease (CJD) caused by the c.598G > A mutation in PRNP encoding a p.Glu200Lys (E200K) substitution in the prion protein. If confirmed, this finding would carry clear implications for genetic counseling. We analyzed pedigrees with this mutation from four prion centers worldwide (n = 217 individuals with the mutation) to analyze age of onset and death in affected and censored individuals. We show through simulation that selective ascertainment of individuals whose onset falls within the historical window since the mutation's 1989 discovery is sufficient to create robust false signals both of anticipation and of heritability of age of onset. In our data set, the number of years of anticipation observed depends upon how strictly the data are limited by the ascertainment window. Among individuals whose disease was directly observed at a study center, a 28-year difference between parent and child age of onset is observed (p = 0.002), but including individuals ascertained retrospectively through family history reduces this figure to 7 years (p = 0.005). Applying survival analysis to the most thoroughly ascertained subset of data eliminates the signal of anticipation. Moreover, even non-CJD deaths exhibit 16 years anticipation (p = 0.002), indicating that ascertainment bias can entirely explain observed anticipation. We suggest that reports of anticipation in genetic prion disease are driven entirely by ascertainment bias. Guidelines for future studies claiming statistical evidence for anticipation are suggested.

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