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Neurology. 2013 Oct 8;81(15):1332-41. doi: 10.1212/WNL.0b013e3182a8250c. Epub 2013 Sep 11.

C9ORF72 repeat expansions in cases with previously identified pathogenic mutations.

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From the Departments of Neuroscience (M.v.B., M.C.B., M.D.-H., M.E.M., N.J.R., P.E.B., T.R., B.M., P.E.A.A., K.F.B., L.P., D.W.D., R.R.) and Neurology (Z.K.W., K.B.B., N.R.G.-R.), Mayo Clinic, Jacksonville, FL; Proteomics Unit and NeuroBioGen Lab-Memory Clinic (R.G., L.B., G.B.), IRCCS Istituto Centro San Giovanni di Dio-Fatebenefratelli, Brescia, Italy; Department of Clinical Neurological Sciences (E.F., M.J.S.), Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Canada; Division of Neurology (G.-Y.R.H.), and Department of Pathology and Laboratory Medicine (I.R.M.), University of British Columbia, Vancouver, Canada; Department of Neurology (B.J.K., D.S.K., R.C.P., B.F.B.), Mayo Clinic, Rochester, MN; Department of Pathology and Alzheimer's Disease Center (K.J.H., C.L.W.), University of Texas Southwestern Medical Center, Dallas; Department of Neurology (A.K., B.L.M.), University of California, San Francisco; Center for Neurodegenerative Disease Research (E.M.W., V.M.V.D.), Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia; Department of Neurology (G.C., D.H.G.), The David Geffen School of Medicine at University of California, Los Angeles; Cognitive Neurology & Alzheimer Disease Center (E.H.B., M.M.), Northwestern University Feinberg School of Medicine, Chicago, IL; Department of Neurology (C.L.), Drexel University College of Medicine, Philadelphia, PA; Molecular Brain Research Group (M.J.S.), Robarts Research Institute, London, Canada; Banner Sun Health Research Institute (T.G.B.), Sun City, AZ; Cognitive Neuroscience Section (E.D.H.), National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD; Departments of Psychiatry and Neurology (E.D.H.), Columbia University, New York; and Department of Neurology (T.B.), University of Washington School of Medicine, Seattle.



To identify potential genetic modifiers contributing to the phenotypic variability that is detected in patients with repeat expansions in chromosome 9 open reading frame 72 (C9ORF72), we investigated the frequency of these expansions in a cohort of 334 subjects previously found to carry mutations in genes known to be associated with a spectrum of neurodegenerative diseases.


A 2-step protocol, with a fluorescent PCR and a repeat-primed PCR, was used to determine the presence of hexanucleotide expansions in C9ORF72. For one double mutant, we performed Southern blots to assess expansion sizes, and immunohistochemistry to characterize neuropathology.


We detected C9ORF72 repeat expansions in 4 of 334 subjects (1.2% [or 1.8% of 217 families]). All these subjects had behavioral phenotypes and also harbored well-known pathogenic mutations in either progranulin (GRN: p.C466LfsX46, p.R493X, p.C31LfsX35) or microtubule-associated protein tau (MAPT: p.P301L). Southern blotting of one double mutant with a p.C466LfsX46 GRN mutation demonstrated a long repeat expansion in brain (>3,000 repeats), and immunohistochemistry showed mixed neuropathology with characteristics of both C9ORF72 expansions and GRN mutations.


Our findings indicate that co-occurrence of 2 evidently pathogenic mutations could contribute to the pleiotropy that is detected in patients with C9ORF72 repeat expansions. These findings suggest that patients with known mutations should not be excluded from further studies, and that genetic counselors should be aware of this phenomenon when advising patients and their family members.

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