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. 2025 Mar 26;272(4):293.
doi: 10.1007/s00415-025-12990-9.

Analysis of C9orf72 repeat length in progressive supranuclear palsy, corticobasal syndrome, corticobasal degeneration, and atypical parkinsonism

David P Vaughan  1   2 , Raquel Real  1   2 , Marte Theilmann Jensen  1   2 , Riona G Fumi  1   2 , Megan Hodgson  1   2 , Edwin Jabbari  1   2 , Danielle Lux  1   2 , Lesley Wu  1   2 ; PROSPECT consortium; MD-GAP; Thomas T Warner  1   2 , Zane Jaunmuktane  2   3 , Tamas Revesz  3   4 , James B Rowe  5 , Jonathan Rohrer  6 , Huw R Morris  7   8
Affiliations

Analysis of C9orf72 repeat length in progressive supranuclear palsy, corticobasal syndrome, corticobasal degeneration, and atypical parkinsonism

David P Vaughan et al. J Neurol. .

Abstract

Background: Pathogenic hexanucleotide repeat expansions in C9orf72 are the commonest genetic cause of frontotemporal dementia and/or amyotrophic lateral sclerosis. There is growing interest in intermediate repeat expansions in C9orf72 and their relationship to a wide range of neurological presentations, including Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy, corticobasal degeneration, and corticobasal syndromes.

Aims: To assess the prevalence of intermediate C9orf72 repeat expansions in a large cohort of prospectively-recruited patients clinically diagnosed with progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and atypical parkinsonism (APS), compared with healthy controls. We also sought to replicate the association between C9orf72 repeat length and CBD in neuropathologically confirmed cases.

Methods: 626 cases, including PSP (n = 366), CBS (n = 130), and APS (n = 53) from the PROSPECT study, and 77 cases with pathologically confirmed CBD were screened for intermediate repeat expansions in C9orf72 using repeat-primed PCR. These were compared to controls from the PROSPECT-M-UK study and from the 1958 Birth Cohort.

Results: There was no difference in the mean or largest allele size in any affected patient group compared with controls. A higher proportion of our affected cohort had large C9orf72 repeat expansions compared to controls, but there was no difference when comparing the frequency of intermediate expansions between affected patients and controls. There was no relationship between repeat length and age at onset, level of disability, or survival.

Conclusions: Intermediate expansions in C9orf72 do not appear to be a genetic risk factor for PSP, CBS, CBD, or atypical parkinsonism. They are not associated with age at onset, disability, or survival in our study.

Keywords: C9orf72; Corticobasal degeneration; Genetics; Parkinsonism; Progressive supranuclear palsy.

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Conflict of interest statement

Declarations. Conflicts of interest: Dr Morris is employed by UCL. In the last 12 months he reports paid consultancy from Aprinoia and AI Therapeutics; lecture fees/honoraria - Movement Disorders Society. Research Grants from Parkinson’s UK, Cure Parkinson’s Trust, PSP Association, Medical Research Council, Michael J Fox Foundation. Dr Morris is a co-applicant on a patent application related to C9orf72 - Method for diagnosing a neurodegenerative disease (PCT/GB2012/052140).

Figures

Fig. 1
Fig. 1
Allele frequencies of C9orf72 repeat sizes in cases and 1958 birth cohort controls. A Histogram showing frequency of each repeat size allele in all affected patients versus controls. B Histogram showing frequency of each repeat size allele in pathologically confirmed CBD patients versus controls
Fig. 2
Fig. 2
Allele frequencies of C9orf72 repeat sizes in cases and 1958 birth cohort controls. Histogram showing frequency of each repeat size allele in all affected patients versus PROSPECT controls
See this image and copyright information in PMC

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