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

Karri Kaivola,Anna Kiviharju,Lilja Jansson,Ville Rantalainen,Johan G Eriksson,Timo E Strandberg,Hannu Laaksovirta,Alan E Renton,Bryan J Traynor,Liisa Myllykangas,Pentti J Tienari

doi:10.1016/j.neurobiolaging.2019.02.026

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.

Highlights

C9orf72 hexanucleotide repeat expansion is a major cause of sporadic and familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (DeJesus-Hernandez et al, 2011; Renton et al, 2011), and it is common in Finland (Majounie et al, 2012)
The C9orf72 hexanucleotide repeat expansion is a major cause of ALS/FTD; what repeat lengths are pathogenic is still unclear
Our data suggest that 30e45 repeat alleles should not be considered unequivocally pathogenic and other risk factors than the C9orf72 expansion should be considered in patients with these alleles

Summary

Introduction

C9orf hexanucleotide repeat expansion is a major cause of sporadic and familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (DeJesus-Hernandez et al, 2011; Renton et al, 2011), and it is common in Finland (Majounie et al, 2012). Expansions can span up to several 1000 repeats, but the minimum length of pathogenic expansion is not known. Knowledge on the distribution of repeat lengths in the general population could help gain a better understanding of the threshold for pathogenicity. Perhaps the most widely used threshold for expansion is 30, defined in one of the original studies describing the C9orf repeat (Renton et al, 2011). Determining a threshold for expansion is complicated by the difficulty of reliably determining repeat lengths, and thresholds reflect more the limitation of used methods than actual alteration in biologic function. Southern blot is considered to be the golden standard of repeat length estimation but because of its high demand of good quality DNA, cost, and work load, often other methods such as repeatprimed PCR (RP-PCR) are used

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Conclusion