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

Neurobiol Aging. 2019 Dec;84:242.e7-242.e12. doi: 10.1016/j.neurobiolaging.2019.02.026. Epub 2019 Mar 11.

Abstract

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.

Keywords: Alzheimer's disease; C9orf72; Cohort studies; Dementia; Genetics.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Amyotrophic Lateral Sclerosis / diagnosis
  • Amyotrophic Lateral Sclerosis / genetics*
  • C9orf72 Protein / genetics*
  • Cognition*
  • Cohort Studies
  • DNA Repeat Expansion*
  • Female
  • Frontotemporal Dementia / diagnosis
  • Frontotemporal Dementia / genetics*
  • Humans
  • Male
  • Middle Aged

Substances

  • C9orf72 Protein
  • C9orf72 protein, human