C9ORF72 repeat expansions in cases with previously identified pathogenic mutations

Marka Van Blitterswijk, Matthew C. Baker, Mariely Hernandez, Roberta Ghidoni, Luisa Benussi, Elizabeth Finger, Ging Yuek R. Hsiung, Brendan J. Kelley, Melissa E. Murray, Nicola J. Rutherford, Patricia E. Brown, Thomas Ravenscroft, Bianca Mullen, Peter E.A. Ash, Kevin F. Bieniek, Kimmo J. Hatanpaa, Anna Karydas, Elisabeth Mc Carty Wood, Giovanni Coppola, Eileen H. BigioCarol Lippa, Michael J. Strong, Thomas G. Beach, David S. Knopman, Edward D. Huey, Marsel Mesulam, Thomas Bird, Charles L. White, Andrew Kertesz, Dan H. Geschwind, Vivianna M. Van Deerlin, Ronald C. Petersen, Giuliano Binetti, Bruce L. Miller, Leonard Petrucelli, Zbigniew K. Wszolek, Kevin B. Boylan, Neill R. Graff-Radford, Ian R. MacKenzie, Bradley F. Boeve, Dennis W. Dickson, Rosa Rademakers

Research output: Contribution to journalArticlepeer-review

76 Scopus citations


Objective: 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. Methods: 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. Results: 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. Conclusions: 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.

Original languageEnglish (US)
Pages (from-to)1332-1341
Number of pages10
Issue number15
StatePublished - Oct 8 2013
Externally publishedYes

ASJC Scopus subject areas

  • Clinical Neurology


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