C9orf72 hexanucleotide repeat length in older population: normal variation and effects on cognition.

Area of Science:

• Genetics
• Neuroscience
• Neurology

Background:

• The hexanucleotide repeat expansion in C9orf72 is a known cause of amyotrophic lateral sclerosis/frontotemporal dementia.
• The precise pathogenic repeat length threshold and the clinical significance of intermediate repeat lengths remain unclear.

Purpose of the Study:

• To determine the repeat length distribution of C9orf72 in a large Finnish cohort.
• To investigate the clinical significance of intermediate and expanded C9orf72 repeat lengths.

Main Methods:

• Genotyping of C9orf72 repeat length in 3142 older Finnish individuals (aged 60-104 years).
• Analysis of disease associations for different repeat length categories.

Main Results:

• The longest non-expanded allele observed was 45 repeats.
• Alleles with 30-45 repeats (0.38%) showed no association with neurodegenerative or psychiatric diseases.
• Intermediate length alleles (7-45 and 20-45 repeats) did not correlate with Alzheimer's disease or cognitive impairment.
• Six individuals carried expansions (>45 repeats), with four diagnosed with neurodegenerative or psychiatric conditions, but none with ALS/FTD.

Conclusions:

• Repeat lengths of 30-45 in C9orf72 are unlikely to be pathogenic.
• Intermediate C9orf72 repeat lengths do not appear to be associated with Alzheimer's disease or cognitive impairment in this cohort.
• While rare expansions exist, their direct link to ALS/FTD requires further investigation.