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- Title
Long-read targeted sequencing uncovers clinicopathological associations for C9orf72-linked diseases.
- Authors
DeJesus-Hernandez, Mariely; Aleff, Ross A; Jackson, Jazmyne L; Finch, NiCole A; Baker, Matthew C; Gendron, Tania F; Murray, Melissa E; McLaughlin, Ian J; Harting, John R; Graff-Radford, Neill R; Oskarsson, Björn; Knopman, David S; Josephs, Keith A; Boeve, Bradley F; Petersen, Ronald C; Fryer, John D; Petrucelli, Leonard; Dickson, Dennis W; Rademakers, Rosa; Ebbert, Mark T W
- Abstract
To examine the length of a hexanucleotide expansion in C9orf72, which represents the most frequent genetic cause of frontotemporal lobar degeneration and motor neuron disease, we employed a targeted amplification-free long-read sequencing technology: No-Amp sequencing. In our cross-sectional study, we assessed cerebellar tissue from 28 well-characterized C9orf72 expansion carriers. We obtained 3507 on-target circular consensus sequencing reads, of which 814 bridged the C9orf72 repeat expansion (23%). Importantly, we observed a significant correlation between expansion sizes obtained using No-Amp sequencing and Southern blotting (P = 5.0 × 10-4). Interestingly, we also detected a significant survival advantage for individuals with smaller expansions (P = 0.004). Additionally, we uncovered that smaller expansions were significantly associated with higher levels of C9orf72 transcripts containing intron 1b (P = 0.003), poly(GP) proteins (P = 1.3 × 10- 5), and poly(GA) proteins (P = 0.005). Thorough examination of the composition of the expansion revealed that its GC content was extremely high (median: 100%) and that it was mainly composed of GGGGCC repeats (median: 96%), suggesting that expanded C9orf72 repeats are quite pure. Taken together, our findings demonstrate that No-Amp sequencing is a powerful tool that enables the discovery of relevant clinicopathological associations, highlighting the important role played by the cerebellar size of the expanded repeat in C9orf72-linked diseases.
- Subjects
FRONTOTEMPORAL lobar degeneration; MOTOR neuron diseases; AMYOTROPHIC lateral sclerosis; NEURODEGENERATION
- Publication
Brain: A Journal of Neurology, 2021, Vol 144, Issue 4, p1082
- ISSN
0006-8950
- Publication type
journal article
- DOI
10.1093/brain/awab006