ArticleAmerican journal of human genetics2015
Jump from pre-mutation to pathologic expansion in C9orf72.
Article in American journal of human genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
31 citing papers in PubMed, 55 citations in OpenAlex.
- Single-nucleus transcriptome atlas of orbitofrontal cortex in ALS with a deep learning-based decoding of alternative polyadenylation mechanisms.Cell genomics · 2025Article
- High-throughput screen of 100 000 small molecules in C9ORF72 ALS neurons identifies spliceosome modulators that mobilize G4C2 repeat RNA into nuclear export and repeat associated non-canonical translation.Nucleic acids research · 2025Article
- Article
- The shared ancestry between the C9orf72 hexanucleotide repeat expansion and intermediate-length alleles using haplotype sharing trees and HAPTK.American journal of human genetics · 2024Article
- Senataxin helicase, the causal gene defect in ALS4, is a significant modifier of C9orf72 ALS G4C2 and arginine-containing dipeptide repeat toxicity.Acta neuropathologica communications · 2023Article
- Biomarker discovery and development for frontotemporal dementia and amyotrophic lateral sclerosis.Brain : a journal of neurology · 2022Review
- Genetic and Epigenetic Interplay Define Disease Onset and Severity in Repeat Diseases.Frontiers in aging neuroscience · 2022Review
- Contribution of rare variant associations to neurodegenerative disease presentation.NPJ genomic medicine · 2021Article
- Genome-wide association study of frontotemporal dementia identifies a C9ORF72 haplotype with a median of 12-G4C2 repeats that predisposes to pathological repeat expansions.Translational psychiatry · 2021Article
- Unravelling the clinical spectrum and the role of repeat length inJournal of neurology, neurosurgery, and psychiatry · 2021Review
- Article
- Intricacies of aetiology in intrafamilial degenerative disease.Brain communications · 2020Review
- Synaptic localization of C9orf72 regulates post-synaptic glutamate receptor 1 levels.Acta neuropathologica communications · 2019Article
- Comprehensive genotyping of the C9orf72 hexanucleotide repeat region in 2095 ALS samples from the NINDS collection using a two-mode, long-read PCR assay.Amyotrophic lateral sclerosis & frontotemporal degeneration · 2019Article
- A Pipeline to Assess Disease-Associated Haplotypes in Repeat Expansion Disorders: The Example of MJD/SCA3Frontiers in genetics · 2019Article
- TheMolecular and cellular biology · 2018Article
- A C6orf10/LOC101929163 locus is associated with age of onset in C9orf72 carriers.Brain : a journal of neurology · 2018Article
- C9orf72-mediated ALS and FTD: multiple pathways to disease.Nature reviews. Neurology · 2018Review
- Disease Mechanisms ofCold Spring Harbor perspectives in medicine · 2018Review
- Unaffected mosaicNeurology · 2018Article
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Authors and funding
24 authors at 4 institutions in 2 countries.
Funding
Abstract
An expanded G4C2 repeat in C9orf72 represents the most common known genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). However, the lower limit for pathological expansions is unknown (the suggested cutoff is 30 repeats). It has been proposed that the expansion might have occurred only once in human history and subsequently spread throughout the population. However, our present findings support a hypothesis of multiple origins for the expansion. We report a British-Canadian family in whom a ∼70-repeat allele from the father (unaffected by ALS or FTLD at age 89 years) expanded during parent-offspring transmission and started the first generation affected by ALS (four children carry an ∼1,750-repeat allele). Epigenetic and RNA-expression analyses further discriminated the offspring's large expansions (which were methylated and associated with reduced C9orf72 expression) from the ∼70-repeat allele (which was unmethylated and associated with upregulation of C9orf72). Moreover, RNA foci were only detected in fibroblasts from offspring with large expansions, but not in the father, who has the ∼70-repeat allele. All family members with expansions were found to have an ancient known risk haplotype, although it was inherited on a unique 5-Mb genetic backbone. We conclude that small expansions (e.g., 70 repeats) might be considered "pre-mutations" to reflect their propensity to expand in the next generation. Follow-up studies might help explain the high frequency of ALS- or FTLD-affected individuals with an expansion but without a familial history (e.g., 21% among Finnish ALS subjects).
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.