TY - JOUR
T1 - Evaluating pathogenic dementia variants in posterior cortical atrophy
AU - Carrasquillo, Minerva M.
AU - Barber, Imelda
AU - Lincoln, Sarah J.
AU - Murray, Melissa E.
AU - Camsari, Gamze Balci
AU - Khan, Qurat ul Ain
AU - Nguyen, Thuy
AU - Ma, Li
AU - Bisceglio, Gina D.
AU - Crook, Julia E.
AU - Younkin, Steven G.
AU - Dickson, Dennis W.
AU - Boeve, Bradley F.
AU - Graff-Radford, Neill R.
AU - Morgan, Kevin
AU - Ertekin-Taner, Nilüfer
N1 - Funding Information:
Support for this research was provided by the National Institutes of Health grants: National Institute on Aging (R01 AG032990 to Nilüfer Ertekin-Taner; U01 AG046139 to Nilüfer Ertekin-Taner and Steven G. Younkin; R01 AG018023 to Neill R. Graff-Radford and Steven G. Younkin; and AG025711, AG017216, AG003949 to Dennis W. Dickson); National Institutes on Neurologic Diseases and Stroke (R01 NS080820 to Nilüfer Ertekin-Taner), Mayo Alzheimer’s Disease Research Center: (P50 AG016574 to Dennis W. Dickson, Neill R. Graff-Radford, Steven G. Younkin, and Nilüfer Ertekin-Taner); Minerva M. Carrasquillo is supported in part by an MNIRGD Alzheimer’s Association grant. Imelda Barber is supported by a Joint Alzheimer’s Research UK and/or University of Nottingham Faculty of Medicine PhD studentship. The work in the KM laboratory is supported by funding from ARUK, and Kevin Morgan is a member of the Alzheimer’s Society Grant Advisory Board. The authors thank the patients and their families for their participation, without whom these studies would not have been possible.
Funding Information:
Support for this research was provided by the National Institutes of Health grants: National Institute on Aging ( R01 AG032990 to Nilüfer Ertekin-Taner; U01 AG046139 to Nilüfer Ertekin-Taner and Steven G. Younkin; R01 AG018023 to Neill R. Graff-Radford and Steven G. Younkin; and AG025711 , AG017216 , AG003949 to Dennis W. Dickson); National Institutes on Neurologic Diseases and Stroke (R01 NS080820 to Nilüfer Ertekin-Taner), Mayo Alzheimer's Disease Research Center: (P50 AG016574 to Dennis W. Dickson, Neill R. Graff-Radford, Steven G. Younkin, and Nilüfer Ertekin-Taner); Minerva M. Carrasquillo is supported in part by an MNIRGD Alzheimer's Association grant. Imelda Barber is supported by a Joint Alzheimer's Research UK and/or University of Nottingham Faculty of Medicine PhD studentship. The work in the KM laboratory is supported by funding from ARUK , and Kevin Morgan is a member of the Alzheimer's Society Grant Advisory Board. The authors thank the patients and their families for their participation, without whom these studies would not have been possible.
Funding Information:
B. Boeve, M.D. has served as an investigator for clinical trials sponsored by Cephalon, Inc, Allon Pharmaceuticals and GE Healthcare, and serves on the Scientific Advisory Board of the Tau Consortium. N. Graff-Radford, M.D. has served as a consultant to Codman and received grant support from Elan Pharmaceutical Research, Pfizer Pharmaceuticals, Medivation, and Forrest.
Publisher Copyright:
© 2016 Elsevier Inc. All rights reserved.
PY - 2016
Y1 - 2016
N2 - Posterior cortical atrophy (PCA) is an understudied visual impairment syndrome most often due to "posterior Alzheimer's disease (AD)" pathology. Case studies detected mutations in PSEN1, PSEN2, GRN, MAPT, and PRNP in subjects with clinical PCA. To detect the frequency and spectrum of mutations in known dementia genes in PCA, we screened 124 European-American subjects with clinical PCA (n = 67) or posterior AD neuropathology (n = 57) for variants in genes implicated in AD, frontotemporal dementia, and prion disease using NeuroX, a customized exome array. Frequencies in PCA of the variants annotated as pathogenic or potentially pathogenic were compared against w4300 European-American population controls from the NHLBI Exome Sequencing Project. We identified 2 rare variants not previously reported in PCA, TREM2 Arg47His, and PSEN2 Ser130Leu. No other pathogenic or potentially pathogenic variants were detected in the screened dementia genes. In this first systematic variant screen of a PCA cohort, we report 2 rare mutations in TREM2 and PSEN2, validate our previously reported APOE e4 association, and demonstrate the utility of NeuroX.
AB - Posterior cortical atrophy (PCA) is an understudied visual impairment syndrome most often due to "posterior Alzheimer's disease (AD)" pathology. Case studies detected mutations in PSEN1, PSEN2, GRN, MAPT, and PRNP in subjects with clinical PCA. To detect the frequency and spectrum of mutations in known dementia genes in PCA, we screened 124 European-American subjects with clinical PCA (n = 67) or posterior AD neuropathology (n = 57) for variants in genes implicated in AD, frontotemporal dementia, and prion disease using NeuroX, a customized exome array. Frequencies in PCA of the variants annotated as pathogenic or potentially pathogenic were compared against w4300 European-American population controls from the NHLBI Exome Sequencing Project. We identified 2 rare variants not previously reported in PCA, TREM2 Arg47His, and PSEN2 Ser130Leu. No other pathogenic or potentially pathogenic variants were detected in the screened dementia genes. In this first systematic variant screen of a PCA cohort, we report 2 rare mutations in TREM2 and PSEN2, validate our previously reported APOE e4 association, and demonstrate the utility of NeuroX.
KW - APOE
KW - Dementia
KW - NeuroX
KW - PCA
KW - PSEN2
KW - Posterior Alzheimer's disease
KW - TREM2
UR - http://www.scopus.com/inward/record.url?scp=84957583628&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84957583628&partnerID=8YFLogxK
U2 - 10.1016/j.neurobiolaging.2015.09.023
DO - 10.1016/j.neurobiolaging.2015.09.023
M3 - Article
C2 - 26507310
AN - SCOPUS:84957583628
SN - 0197-4580
VL - 37
SP - 38
EP - 44
JO - Neurobiology of Aging
JF - Neurobiology of Aging
ER -