Discovery and validation of autosomal dominant Alzheimer's disease mutations

Simon Hsu; Brian A. Gordon; Russ Hornbeck; Joanne B. Norton; Denise Levitch; Adia Louden; Ellen Ziegemeier; Robert Laforce; Jasmeer Chhatwal; Gregory S. Day; Eric McDade; John C. Morris; Anne M. Fagan; Tammie L.S. Benzinger; Alison M. Goate; Carlos Cruchaga; Randall J. Bateman; Celeste M. Karch

doi:10.1186/s13195-018-0392-9

Discovery and validation of autosomal dominant Alzheimer's disease mutations

Simon Hsu, Brian A. Gordon, Russ Hornbeck, Joanne B. Norton, Denise Levitch, Adia Louden, Ellen Ziegemeier, Robert Laforce, Jasmeer Chhatwal, Gregory S. Day, Eric McDade, John C. Morris, Anne M. Fagan, Tammie L.S. Benzinger, Alison M. Goate, Carlos Cruchaga, Randall J. Bateman, Celeste M. Karch

Research output: Contribution to journal › Article › peer-review

30 Scopus citations

Abstract

Background: Alzheimer's disease (AD) is a neurodegenerative disease that is clinically characterized by progressive cognitive decline. Mutations in amyloid-β precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) are the pathogenic cause of autosomal dominant AD (ADAD). However, polymorphisms also exist within these genes. Methods: In order to distinguish polymorphisms from pathogenic mutations, the DIAN Expanded Registry has implemented an algorithm for determining ADAD pathogenicity using available information from multiple domains, including genetic, bioinformatic, clinical, imaging, and biofluid measures and in vitro analyses. Results: We propose that PSEN1 M84V, PSEN1 A396T, PSEN2 R284G, and APP T719N are likely pathogenic mutations, whereas PSEN1 c.379-382delXXXXinsG and PSEN2 L238F have uncertain pathogenicity. Conclusions: In defining a subset of these variants as pathogenic, individuals from these families can now be enrolled in observational and clinical trials. This study outlines a critical approach for translating genetic data into meaningful clinical outcomes.

Original language	English
Article number	67
Journal	Alzheimer's Research and Therapy
Volume	10
Issue number	1
DOIs	https://doi.org/10.1186/s13195-018-0392-9
State	Published - 18 Jul 2018

Keywords

APP
Autosomal dominant Alzheimer's disease
Cell-based assays
PSEN1
PSEN2
Pathogenicity algorithm

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10.1186/s13195-018-0392-9

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Hsu, S., Gordon, B. A., Hornbeck, R., Norton, J. B., Levitch, D., Louden, A., Ziegemeier, E., Laforce, R., Chhatwal, J., Day, G. S., McDade, E., Morris, J. C., Fagan, A. M., Benzinger, T. L. S., Goate, A. M., Cruchaga, C., Bateman, R. J., & Karch, C. M. (2018). Discovery and validation of autosomal dominant Alzheimer's disease mutations. Alzheimer's Research and Therapy, 10(1), Article 67. https://doi.org/10.1186/s13195-018-0392-9

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title = "Discovery and validation of autosomal dominant Alzheimer's disease mutations",

abstract = "Background: Alzheimer's disease (AD) is a neurodegenerative disease that is clinically characterized by progressive cognitive decline. Mutations in amyloid-β precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) are the pathogenic cause of autosomal dominant AD (ADAD). However, polymorphisms also exist within these genes. Methods: In order to distinguish polymorphisms from pathogenic mutations, the DIAN Expanded Registry has implemented an algorithm for determining ADAD pathogenicity using available information from multiple domains, including genetic, bioinformatic, clinical, imaging, and biofluid measures and in vitro analyses. Results: We propose that PSEN1 M84V, PSEN1 A396T, PSEN2 R284G, and APP T719N are likely pathogenic mutations, whereas PSEN1 c.379-382delXXXXinsG and PSEN2 L238F have uncertain pathogenicity. Conclusions: In defining a subset of these variants as pathogenic, individuals from these families can now be enrolled in observational and clinical trials. This study outlines a critical approach for translating genetic data into meaningful clinical outcomes.",

keywords = "APP, Autosomal dominant Alzheimer's disease, Cell-based assays, PSEN1, PSEN2, Pathogenicity algorithm",

author = "Simon Hsu and Gordon, {Brian A.} and Russ Hornbeck and Norton, {Joanne B.} and Denise Levitch and Adia Louden and Ellen Ziegemeier and Robert Laforce and Jasmeer Chhatwal and Day, {Gregory S.} and Eric McDade and Morris, {John C.} and Fagan, {Anne M.} and Benzinger, {Tammie L.S.} and Goate, {Alison M.} and Carlos Cruchaga and Bateman, {Randall J.} and Karch, {Celeste M.}",

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year = "2018",

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doi = "10.1186/s13195-018-0392-9",

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Hsu, S, Gordon, BA, Hornbeck, R, Norton, JB, Levitch, D, Louden, A, Ziegemeier, E, Laforce, R, Chhatwal, J, Day, GS, McDade, E, Morris, JC, Fagan, AM, Benzinger, TLS, Goate, AM, Cruchaga, C, Bateman, RJ & Karch, CM 2018, 'Discovery and validation of autosomal dominant Alzheimer's disease mutations', Alzheimer's Research and Therapy, vol. 10, no. 1, 67. https://doi.org/10.1186/s13195-018-0392-9

TY - JOUR

T1 - Discovery and validation of autosomal dominant Alzheimer's disease mutations

AU - Hsu, Simon

AU - Gordon, Brian A.

AU - Hornbeck, Russ

AU - Norton, Joanne B.

AU - Levitch, Denise

AU - Louden, Adia

AU - Ziegemeier, Ellen

AU - Laforce, Robert

AU - Chhatwal, Jasmeer

AU - Day, Gregory S.

AU - McDade, Eric

AU - Morris, John C.

AU - Fagan, Anne M.

AU - Benzinger, Tammie L.S.

AU - Goate, Alison M.

AU - Cruchaga, Carlos

AU - Bateman, Randall J.

AU - Karch, Celeste M.

PY - 2018/7/18

Y1 - 2018/7/18

N2 - Background: Alzheimer's disease (AD) is a neurodegenerative disease that is clinically characterized by progressive cognitive decline. Mutations in amyloid-β precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) are the pathogenic cause of autosomal dominant AD (ADAD). However, polymorphisms also exist within these genes. Methods: In order to distinguish polymorphisms from pathogenic mutations, the DIAN Expanded Registry has implemented an algorithm for determining ADAD pathogenicity using available information from multiple domains, including genetic, bioinformatic, clinical, imaging, and biofluid measures and in vitro analyses. Results: We propose that PSEN1 M84V, PSEN1 A396T, PSEN2 R284G, and APP T719N are likely pathogenic mutations, whereas PSEN1 c.379-382delXXXXinsG and PSEN2 L238F have uncertain pathogenicity. Conclusions: In defining a subset of these variants as pathogenic, individuals from these families can now be enrolled in observational and clinical trials. This study outlines a critical approach for translating genetic data into meaningful clinical outcomes.

AB - Background: Alzheimer's disease (AD) is a neurodegenerative disease that is clinically characterized by progressive cognitive decline. Mutations in amyloid-β precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) are the pathogenic cause of autosomal dominant AD (ADAD). However, polymorphisms also exist within these genes. Methods: In order to distinguish polymorphisms from pathogenic mutations, the DIAN Expanded Registry has implemented an algorithm for determining ADAD pathogenicity using available information from multiple domains, including genetic, bioinformatic, clinical, imaging, and biofluid measures and in vitro analyses. Results: We propose that PSEN1 M84V, PSEN1 A396T, PSEN2 R284G, and APP T719N are likely pathogenic mutations, whereas PSEN1 c.379-382delXXXXinsG and PSEN2 L238F have uncertain pathogenicity. Conclusions: In defining a subset of these variants as pathogenic, individuals from these families can now be enrolled in observational and clinical trials. This study outlines a critical approach for translating genetic data into meaningful clinical outcomes.

KW - APP

KW - Autosomal dominant Alzheimer's disease

KW - Cell-based assays

KW - PSEN1

KW - PSEN2

KW - Pathogenicity algorithm

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DO - 10.1186/s13195-018-0392-9

M3 - Article

C2 - 30021643

AN - SCOPUS:85050349047

SN - 1758-9193

VL - 10

JO - Alzheimer's Research and Therapy

JF - Alzheimer's Research and Therapy

IS - 1

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ER -

Discovery and validation of autosomal dominant Alzheimer's disease mutations

Abstract

Keywords

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