Intergenerational instability of the C9orf72 hexanucleotide repeat
- 1University of Helsinki
Abstract
The C9orf72 hexanucleotide repeat expansion (HRE) is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). It follows autosomal dominant inheritance in families, however, a high proportion of cases are sporadic, raising the possibility of parental premutation. We have demonstrated that intermediate-length alleles (IAs) with >18 repeats (allele frequency ~1%) belong to the same pool of haplotypes as the HRE, suggesting shared ancestry. Here, we tested whether alleles with >18 repeats expand in parental transmission. We used two repeat-primed PCR methods to analyze allele lengths in 539 genetically unselected parent-offspring pairs and in 152 pairs known to carry the SNP (rs139185008*C) that tags >18 repeat IAs and the HRE in Finland. We discovered intergenerational repeat length changes only in >20 repeat alleles. A significant (P = 0.0059) sex bias in 6-40 repeat alleles was noted using a logistic regression model. In this allele range, 12 out of 16 expansions were paternally inherited and 6 out of 7 contractions were maternally inherited. The expansion rate of 20-40 repeat alleles was 34 % in paternal and 11 % in maternal transmissions. In the 20-40 repeat range, most intergenerational expansions were 1-4 repeats in size (15/16), but one larger jump, a paternal expansion from 27 to 73 repeats, was observed. These results demonstrate that alleles with >20 repeats have an increased likelihood of instability, that a paternal expansion bias is observed in alleles with 20-40 repeats, and that expansion events are predominantly 1-4 repeats in size.
Related
- Effects of transcription units and a specific hexanucleotide motif of porcine circovirus-like virus P1 on viral DNA synthesis, viral protein expression, and progeny virus production.
- Disrupted mannosidase enzymes in C9orf72 ALS/FTD
- Temporal RNA splicing dysregulation in a human multicellular model of C9orf72 ALS
- Probing the interaction between the WDR41 7CD loop of the C9ORF72 complex and purified PQLC2
- Integrated Multiomics Reveals Intergenerational Brain Sensory System Remodeling Induced by Parental Intermittent Fasting
BibTeX
@misc{rautila2026intergenerational,
title = {{Intergenerational instability of the C9orf72 hexanucleotide repeat}},
author = {O. S. Rautila and A. Kiviharju and L. Jansson and FinnGen and K. Kaivola and P. J. Tienari},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.10.750611},
url = {https://www.biorxiv.org/content/10.64898/2026.09.10.750611v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Intergenerational instability of the C9orf72 hexanucleotide repeat
AU - O. S. Rautila
AU - A. Kiviharju
AU - L. Jansson
AU - FinnGen
AU - K. Kaivola
AU - P. J. Tienari
PY - 2026
DA - 2026/09/10
PB - bioRxiv
DO - 10.64898/2026.09.10.750611
UR - https://www.biorxiv.org/content/10.64898/2026.09.10.750611v1
AB - The C9orf72 hexanucleotide repeat expansion (HRE) is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). It follows autosomal dominant inheritance in families, however, a high proportion of cases are sporadic, raising the possibility of parental premutation. We have demonstrated that intermediate-length alleles (IAs) with >18 repeats (allele frequency ~1%) belong to the same pool of haplotypes as the HRE, suggesting shared ancestry. Here, we tested whether alleles with >18 repeats expand in parental transmission. We used two repeat-primed PCR methods to analyze allele lengths in 539 genetically unselected parent-offspring pairs and in 152 pairs known to carry the SNP (rs139185008*C) that tags >18 repeat IAs and the HRE in Finland. We discovered intergenerational repeat length changes only in >20 repeat alleles. A significant (P = 0.0059) sex bias in 6-40 repeat alleles was noted using a logistic regression model. In this allele range, 12 out of 16 expansions were paternally inherited and 6 out of 7 contractions were maternally inherited. The expansion rate of 20-40 repeat alleles was 34 % in paternal and 11 % in maternal transmissions. In the 20-40 repeat range, most intergenerational expansions were 1-4 repeats in size (15/16), but one larger jump, a paternal expansion from 27 to 73 repeats, was observed. These results demonstrate that alleles with >20 repeats have an increased likelihood of instability, that a paternal expansion bias is observed in alleles with 20-40 repeats, and that expansion events are predominantly 1-4 repeats in size.
ER -