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

The hexanucleotide repeat expansion in C9orf72 is a common cause of amyotrophic lateral sclerosis/frontotemporal dementia and also rarely found in other psychiatric and neurodegenerative conditions. Alleles with >30 repeats are often considered an expansion, but the pathogenic repeat length threshold is still unclear. It is also unclear whether intermediate repeat length alleles (often defined either as 7–30 or 20–30 repeats) have clinically significant effects. We determined the C9orf72 repeat length distribution in 3142 older Finns (aged 60–104 years). The longest nonexpanded allele was 45 repeats. We found 7–45 repeats in 1036/3142 (33%) individuals, 20–45 repeats in 56/3142 (1.8%), 30–45 repeats in 12/3142 (0.38%), and expansion (>45 repeats) in 6/3142 (0.19%). There was no apparent clustering of neurodegenerative or psychiatric diseases in individuals with 30–45 repeats indicating that 30–45 repeats are not pathogenic. None of the 6 expansion carriers had a diagnosis of amyotrophic lateral sclerosis/frontotemporal dementia but 4 had a diagnosis of a neurodegenerative or psychiatric disease. Intermediate length alleles (categorized as 7–45 and 20–45 repeats) did not associate with Alzheimer's disease or cognitive impairment.