GGGGCC hexanucleotide repeat expansion in the C9ORF72 gene (C9ORF72 HRE)

The GGGGCC hexanucleotide repeat expansion (HRE) in the first intron of the C9ORF72 gene is the most prevalent genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (NIH, 2024). While healthy individuals typically possess fewer than 30 repeats, affected patients can harbor hundreds or thousands, leading to neurodegeneration through a combination of loss-of-function and gain-of-function mechanisms (Frontiers in Neuroscience, 2023). Pathogenesis involves the formation of toxic RNA foci that sequester essential RNA-binding proteins and the production of dipeptide repeat proteins (DPRs) through repeat-associated non-AUG (RAN) translation (NIH, 2021). Therapeutic efforts have primarily focused on antisense oligonucleotides (ASOs) designed to degrade the repeat-containing transcripts, although major candidates like BIIB078 and WVE-004 were discontinued after failing to show clinical benefit in trials (FierceBiotech, 2023; Biogen, 2022). Current research continues to explore small molecules that stabilize G-quadruplex structures, gene-editing techniques like CRISPR/Cas9 to remove the expansion, and therapies aimed at reducing toxic DPR levels (MDPI, 2025; ALS Association, 2017).

Other names

G4C2 repeat expansionC9orf72 repeat expansionGGGGCC repeatC9+ mutationChromosome 9 open reading frame 72 repeat expansion

Antisense oligonucleotide-mediated RNase H degradation of repeat-containing RNA transcripts (NIH, 2024); small molecule inhibition of repeat-associated non-AUG (RAN) translation (NIH, 2020); CRISPR/Cas9-mediated excision of the genomic expansion (Frontiers, 2023).