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Am J Neurodegener Dis 2012;1(1):107-118

Original Article
C9ORF72 repeat expansions and other FTD gene mutations in a clinical
AD patient series from Mayo Clinic

Aleksandra Wojtas, Kristin A Heggeli, NiCole Finch, Matt Baker, Mariely DeJesus-Hernandez, Steven G Younkin,
Dennis W Dickson, Neill R Graff-Radford, Rosa Rademakers

Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA; Department of Neurology, Mayo Clinic, Jacksonville,

Received May 8, 2012; accepted May, 2012; Epub May, 2012; published May 30, 2012

Abstract: Alzheimer disease (AD) and frontotemporal dementia (FTD) are two frequent forms of primary
neurodegenerative dementias with overlapping clinical symptoms. Pathogenic mutations of the amyloid precursor
protein (APP) and presenilins 1 and 2 (PSEN1, PSEN2) genes have been linked to familial early-onset forms of AD;
however, more recently mutations in the common FTD genes encoding the microtubule associated protein tau (MAPT),
progranulin (GRN) and C9ORF72, have also been reported in clinically diagnosed AD patients. To access the
contribution of mutations in a well-characterized series of patients, we systematically performed genetic analyses of
these EOAD and FTD genes in a novel cohort of 227 unrelated probands clinically diagnosed as probable AD which
were ascertained at Mayo Clinic Florida between 1997 and 2011. All patients showed first symptoms of dementia
before 70 years.  We identified 9 different pathogenic mutations in the EOAD genes in a total of 11 patients explaining
4.8% of the patient population. Two mutations were novel: PSEN1 p.Pro218Leu and PSEN2 p.Phe183Ser. Importantly,
mutations were also identified in all FTD genes: one patient carried a MAPT p.R406W mutation, one patient carried the
p.Arg198Glyfs19X loss-of-function mutation in GRN and two patients were found to carry expanded GGGGCC repeats
in the non-coding region of C9ORF72. Together the FTD genes explained the disease in 1.8% of our probable AD
population. The identification of mutations in all major FTD genes in this novel cohort of clinically diagnosed AD
patients underlines the challenges associated with the differential diagnosis of AD and FTD resulting from overlapping
symptomatology and has important implications for molecular diagnostic testing and genetic counseling of clinically
diagnosed AD patients. Our findings suggest that in clinically diagnosed AD patients, genetic analyses should include
not only the well-established EOAD genes APP, PSEN1 and PSEN2 but also genes that are usually associated with
FTD. Finally, the overall low frequency of mutation carriers observed in our study (6.6%) suggests the involvement of
other as yet unknown genetic factors associated with AD. (AJND1105001)

Keywords: Alzheimer’s disease, frontotemporal dementia, amyloid precursor protein, presenilin 1, presenilin 2,
progranulin, microtubule associated protein tau, C9ORF72, mutation, diagnosis

Address all correspondence to:
Dr. Rosa Rademakers
Department of Neuroscience
Mayo Clinic College of Medicine
4500 San Pablo Road, Jacksonville, FL 32224, USA.
Phone: (904) 953-6279; Fax: (904) 953-7370
E-mail: Rademakers.rosa@mayo.edu