Evaluating the causality of novel sequence variants in the prion protein gene by example
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Evaluating the causality of novel sequence variants in the prion protein gene by example. / Mok, Tze How; Koriath, Carolin; Jaunmuktane, Zane; Campbell, Tracy; Joiner, Susan; Wadsworth, Jonathan D F; Hosszu, Laszlo L P; Brandner, Sebastian; Parvez, Ambereen; Truelsen, Thomas Clement; Lund, Eva Løbner; Saha, Romi; Collinge, John; Mead, Simon.
I: Neurobiology of Aging, Bind 71, 2018, s. 265.e1-265.e7.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - Evaluating the causality of novel sequence variants in the prion protein gene by example
AU - Mok, Tze How
AU - Koriath, Carolin
AU - Jaunmuktane, Zane
AU - Campbell, Tracy
AU - Joiner, Susan
AU - Wadsworth, Jonathan D F
AU - Hosszu, Laszlo L P
AU - Brandner, Sebastian
AU - Parvez, Ambereen
AU - Truelsen, Thomas Clement
AU - Lund, Eva Løbner
AU - Saha, Romi
AU - Collinge, John
AU - Mead, Simon
N1 - Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
PY - 2018
Y1 - 2018
N2 - The estimation of pathogenicity and penetrance of novel prion protein gene (PRNP) variants presents significant challenges, particularly in the absence of family history, which precludes the application of Mendelian segregation. Moreover, the ambiguities of prion disease pathophysiology renders conventional in silico predictions inconclusive. Here, we describe 2 patients with rapid cognitive decline progressing to akinetic mutism and death within 10 weeks of symptom onset, both of whom possessed the novel T201S variant in PRNP. Clinically, both satisfied diagnostic criteria for probable sporadic Creutzfeldt-Jakob disease and in one, the diagnosis was confirmed by neuropathology. While computational analyses predicted that T201S was possibly deleterious, molecular strain typing, prion protein structural considerations, and calculations leveraging large-scale population data (gnomAD) indicate that T201S is at best either of low penetrance or nonpathogenic. Thus, we illustrate the utility of harnessing multiple lines of prion disease-specific evidence in the evaluation of the T201S variant, which may be similarly applied to assess other novel variants in PRNP.
AB - The estimation of pathogenicity and penetrance of novel prion protein gene (PRNP) variants presents significant challenges, particularly in the absence of family history, which precludes the application of Mendelian segregation. Moreover, the ambiguities of prion disease pathophysiology renders conventional in silico predictions inconclusive. Here, we describe 2 patients with rapid cognitive decline progressing to akinetic mutism and death within 10 weeks of symptom onset, both of whom possessed the novel T201S variant in PRNP. Clinically, both satisfied diagnostic criteria for probable sporadic Creutzfeldt-Jakob disease and in one, the diagnosis was confirmed by neuropathology. While computational analyses predicted that T201S was possibly deleterious, molecular strain typing, prion protein structural considerations, and calculations leveraging large-scale population data (gnomAD) indicate that T201S is at best either of low penetrance or nonpathogenic. Thus, we illustrate the utility of harnessing multiple lines of prion disease-specific evidence in the evaluation of the T201S variant, which may be similarly applied to assess other novel variants in PRNP.
U2 - 10.1016/j.neurobiolaging.2018.05.011
DO - 10.1016/j.neurobiolaging.2018.05.011
M3 - Journal article
C2 - 29861043
VL - 71
SP - 265.e1-265.e7
JO - Neurobiology of Aging
JF - Neurobiology of Aging
SN - 0197-4580
ER -
ID: 216505276