Evaluating the causality of novel sequence variants in the prion protein gene by example

TY - JOUR

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 - 2018/11

Y1 - 2018/11

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

SN - 0197-4580

VL - 71

SP - 265.e1-265.e7

JO - Neurobiology of Aging

JF - Neurobiology of Aging

ER -