Preprint: C9orf72 intermediate alleles expand in parental transmission, suggesting a premutation route to ALS and FTD
A bioRxiv preprint presents evidence that C9orf72 alleles carrying more than 18 hexanucleotide repeats are unstable across generations and can expand toward the pathogenic range, offering a possible explanation for the high rate of apparently sporadic ALS and frontotemporal dementia.
The C9orf72 hexanucleotide repeat expansion (HRE) is the most common identified genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), and it segregates in an autosomal dominant pattern in multi-generational families. A persistent puzzle, however, is that a large proportion of C9orf72-associated cases appear sporadic — arising without a family history consistent with dominant inheritance. A preprint deposited on bioRxiv on 15 September 2026 addresses this directly.
The authors report that intermediate-length alleles (IAs) carrying more than 18 repeats — present at an allele frequency of approximately 1% — share haplotype backgrounds with confirmed pathogenic expansions, implying a common ancestral origin. Using two repeat-primed PCR methods, they then tested directly whether these intermediate alleles expand during parental transmission. The data indicate that they do, supporting a premutation model analogous to those established for other repeat-expansion disorders such as fragile X syndrome and myotonic dystrophy.
If confirmed, these findings would have implications for genetic counselling in families where an index case carries an intermediate allele, and for understanding population-level incidence of ALS and FTD. As a preprint, the work has not yet been peer-reviewed and the results should be treated as preliminary. The study was deposited under a CC BY licence.
Plain-language version
For patients, families, and general readers. Educational only — not medical advice.
The C9orf72 gene contains a short repeated sequence of DNA letters. When this repeat grows very long — an expansion — it is the most common known genetic cause of the motor neurone disease ALS and a condition called frontotemporal dementia (FTD). Many cases occur in people with no family history of these conditions, which has puzzled scientists.
A new study (not yet peer-reviewed) suggests the reason may be that some people carry an intermediate number of repeats — not long enough to cause disease itself, but potentially capable of growing longer when passed to a child. The researchers found that these intermediate sequences appear to come from the same ancestral lineage as the full expansions, and show signs of expanding across generations.
If the findings hold up after independent review, they could be relevant to genetic counselling in some families. This research is at an early stage.
This is an educational summary, not medical advice. If anything here raises questions for you, please speak with your GP or a clinical professional.
Sources
Read the original reporting — these are the public sources this summary draws from.
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Primary sourcePreprint bioRxiv (Cold Spring Harbor Laboratory) · 2026-09-15Intergenerational instability of the C9orf72 hexanucleotide repeat