Evaluating pathogenic dementia variants in posterior cortical atrophy.
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 ∼ 4300 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 ε4 association, and demonstrate the utility of NeuroX.
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Minerva M
MM
Carrasquillo
Human Genetics Group, University of Nottingham, Nottingham, UK.
Imelda
I
Barber
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Sarah J
SJ
Lincoln
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Melissa E
ME
Murray
Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
Gamze Balci
GB
Camsari
Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
Qurat Ul Ain
QUA
Khan
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Thuy
T
Nguyen
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Li
L
Ma
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Gina D
GD
Bisceglio
Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, USA.
Julia E
JE
Crook
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Steven G
SG
Younkin
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Dennis W
DW
Dickson
Department of Neurology, Mayo Clinic, Rochester, MN, USA.
Bradley F
BF
Boeve
Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
Neill R
NR
Graff-Radford
Human Genetics Group, University of Nottingham, Nottingham, UK.
Kevin
K
Morgan
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA; Department of Neurology, Mayo Clinic, Jacksonville, FL, USA. Electronic address: taner.nilufer@mayo.edu.
Nilüfer
N
Ertekin-Taner
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics*; D015331:Cohort Studies; D059472:Exome / Q000235:genetics; D005260:Female; D005838:Genotype; D060005:Genotyping Techniques / Q000379:methods; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D053766:Presenilin-2 / Q000235:genetics*; D011971:Receptors, Immunologic / Q000235:genetics*; D013577:Syndrome; D014786:Vision Disorders / Q000235:genetics*
D008562:Membrane Glycoproteins; C508861:PSEN2 protein, human; D053766:Presenilin-2; D011971:Receptors, Immunologic; C498715:TREM2 protein, human
APOE; Dementia; NeuroX; PCA; PSEN2; Posterior Alzheimer's disease; TREM2