Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2
Alzheimer's disease (AD) is a neurodegenerative disease that is clinically characterized by progressive cognitive decline. More than 200 pathogenic mutations have been identified in amyloid-β precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2). Additionally, common and rare v...
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doaj-6c0aaa906c664eaa875e9d84952559192021-03-22T08:41:41ZengElsevierNeurobiology of Disease1095-953X2020-06-01139104817Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2Simon Hsu0Anna A. Pimenova1Kimberly Hayes2Juan A. Villa3Matthew J. Rosene4Madhavi Jere5Alison M. Goate6Celeste M. Karch7Department of Psychiatry, Washington University School of Medicine, 425 S Euclid Avenue, St Louis, MO 63110, USADepartment of Neuroscience, Mount Sinai School of Medicine, New York, NY, USADepartment of Psychiatry, Washington University School of Medicine, 425 S Euclid Avenue, St Louis, MO 63110, USADepartment of Psychiatry, Washington University School of Medicine, 425 S Euclid Avenue, St Louis, MO 63110, USADepartment of Psychiatry, Washington University School of Medicine, 425 S Euclid Avenue, St Louis, MO 63110, USADepartment of Psychiatry, Washington University School of Medicine, 425 S Euclid Avenue, St Louis, MO 63110, USADepartment of Neuroscience, Mount Sinai School of Medicine, New York, NY, USADepartment of Psychiatry, Washington University School of Medicine, 425 S Euclid Avenue, St Louis, MO 63110, USA; Corresponding author at: Department of Psychiatry, Washington University School of Medicine, 425 S. Euclid Ave, Campus Box 8134, St. Louis, MO 63110, USA.Alzheimer's disease (AD) is a neurodegenerative disease that is clinically characterized by progressive cognitive decline. More than 200 pathogenic mutations have been identified in amyloid-β precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2). Additionally, common and rare variants occur within APP, PSEN1, and PSEN2 that may be risk factors, protective factors, or benign, non-pathogenic polymorphisms. Yet, to date, no single study has carefully examined the effect of all of the variants of unknown significance reported in APP, PSEN1 and PSEN2 on Aβ isoform levels in vitro. In this study, we analyzed Aβ isoform levels by ELISA in a cell-based system in which each reported pathogenic and risk variant in APP, PSEN1, and PSEN2 was expressed individually. In order to classify variants for which limited family history data is available, we have implemented an algorithm for determining pathogenicity using available information from multiple domains, including genetic, bioinformatic, and in vitro analyses. We identified 90 variants of unknown significance and classified 19 as likely pathogenic mutations. We also propose that five variants are possibly protective. In defining a subset of these variants as pathogenic, individuals from these families may eligible to enroll in observational studies and clinical trials.http://www.sciencedirect.com/science/article/pii/S0969996120300929APPPSEN1PSEN2Alzheimer's diseaseCell-based assaysPathogenicity algorithm |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Simon Hsu Anna A. Pimenova Kimberly Hayes Juan A. Villa Matthew J. Rosene Madhavi Jere Alison M. Goate Celeste M. Karch |
spellingShingle |
Simon Hsu Anna A. Pimenova Kimberly Hayes Juan A. Villa Matthew J. Rosene Madhavi Jere Alison M. Goate Celeste M. Karch Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2 Neurobiology of Disease APP PSEN1 PSEN2 Alzheimer's disease Cell-based assays Pathogenicity algorithm |
author_facet |
Simon Hsu Anna A. Pimenova Kimberly Hayes Juan A. Villa Matthew J. Rosene Madhavi Jere Alison M. Goate Celeste M. Karch |
author_sort |
Simon Hsu |
title |
Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2 |
title_short |
Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2 |
title_full |
Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2 |
title_fullStr |
Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2 |
title_full_unstemmed |
Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2 |
title_sort |
systematic validation of variants of unknown significance in app, psen1 and psen2 |
publisher |
Elsevier |
series |
Neurobiology of Disease |
issn |
1095-953X |
publishDate |
2020-06-01 |
description |
Alzheimer's disease (AD) is a neurodegenerative disease that is clinically characterized by progressive cognitive decline. More than 200 pathogenic mutations have been identified in amyloid-β precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2). Additionally, common and rare variants occur within APP, PSEN1, and PSEN2 that may be risk factors, protective factors, or benign, non-pathogenic polymorphisms. Yet, to date, no single study has carefully examined the effect of all of the variants of unknown significance reported in APP, PSEN1 and PSEN2 on Aβ isoform levels in vitro. In this study, we analyzed Aβ isoform levels by ELISA in a cell-based system in which each reported pathogenic and risk variant in APP, PSEN1, and PSEN2 was expressed individually. In order to classify variants for which limited family history data is available, we have implemented an algorithm for determining pathogenicity using available information from multiple domains, including genetic, bioinformatic, and in vitro analyses. We identified 90 variants of unknown significance and classified 19 as likely pathogenic mutations. We also propose that five variants are possibly protective. In defining a subset of these variants as pathogenic, individuals from these families may eligible to enroll in observational studies and clinical trials. |
topic |
APP PSEN1 PSEN2 Alzheimer's disease Cell-based assays Pathogenicity algorithm |
url |
http://www.sciencedirect.com/science/article/pii/S0969996120300929 |
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