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Semi-automated quantification of C9orf72 expansion size reveals inverse correlation between hexanucleotide repeat number and disease duration in frontotemporal degeneration

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Abstract

We investigated whether chromosome 9 open reading frame 72 hexanucleotide repeat expansion (C9orf72 expansion) size in peripheral DNA was associated with clinical differences in frontotemporal degeneration (FTD) and amyotrophic lateral sclerosis (ALS) linked to C9orf72 repeat expansion mutations. A novel quantification workflow was developed to measure C9orf72 expansion size by Southern blot densitometry in a cross-sectional cohort of C9orf72 expansion carriers with FTD (n = 39), ALS (n = 33), both (n = 35), or who are unaffected (n = 21). Multivariate linear regressions were performed to assess whether C9orf72 expansion size from peripheral DNA was associated with clinical phenotype, age of disease onset, disease duration and age at death. Mode values of C9orf72 expansion size were significantly shorter in FTD compared to ALS (p = 0.0001) but were not associated with age at onset in either FTD or ALS. A multivariate regression model correcting for patient’s age at DNA collection and disease phenotype revealed that C9orf72 expansion size is significantly associated with shorter disease duration (p = 0.0107) for individuals with FTD, but not with ALS. Despite considerable somatic instability of the C9orf72 expansion, semi-automated expansion size measurements demonstrated an inverse relationship between C9orf72 expansion size and disease duration in patients with FTD. Our finding suggests that C9orf72 repeat size may be a molecular disease modifier in FTD linked to hexanucleotide repeat expansion.

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Acknowledgments

We would like to thank the patients and their families for their meaningful contributions that made this study possible. This study was supported by National Institute of Health (NIH) Grants P01 AG032953, PO1 AG017586, P30 AG010124, K01 AG043503, K08 AG039510, K23 NS088341, NIH T32MH065218, and the Doris Duke Charitable Foundation Clinical Scientist Development Award (EBL) and the Wyncote Foundation (CTM).

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    Authors and Affiliations

    1. Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, 3600 Spruce Street, Philadelphia, PA, 19104-4283, USA

      EunRan Suh, Edward B. Lee, Donald Neal, Elisabeth M. Wood, Jon B. Toledo, David J. Irwin, John Q. Trojanowski & Vivianna M. Van Deerlin

    2. Translational Neuropathology Research Laboratory, Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

      Edward B. Lee

    3. Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

      Lior Rennert & Sharon X. Xie

    4. Department of Neurology, Penn Frontotemporal Degeneration Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

      David J. Irwin, Corey T. McMillan & Murray Grossman

    5. Department of Pathology, School of Medicine, University of Utah, Salt Lake City, UT, USA

      Bryan Krock

    6. Department of Neurology, Penn ALS Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

      Lauren B. Elman & Leo F. McCluskey

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    E. R. Suh and E. B. Lee contributed equally to this work.

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    Suh, E., Lee, E.B., Neal, D. et al. Semi-automated quantification of C9orf72 expansion size reveals inverse correlation between hexanucleotide repeat number and disease duration in frontotemporal degeneration. Acta Neuropathol 130, 363–372 (2015). https://doi.org/10.1007/s00401-015-1445-9

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