A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-linked ALS-FTD

Neuron. 2011 Oct 20;72(2):257-68. doi: 10.1016/j.neuron.2011.09.010. Epub 2011 Sep 21.

Abstract

The chromosome 9p21 amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) locus contains one of the last major unidentified autosomal-dominant genes underlying these common neurodegenerative diseases. We have previously shown that a founder haplotype, covering the MOBKL2b, IFNK, and C9ORF72 genes, is present in the majority of cases linked to this region. Here we show that there is a large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72 on the affected haplotype. This repeat expansion segregates perfectly with disease in the Finnish population, underlying 46.0% of familial ALS and 21.1% of sporadic ALS in that population. Taken together with the D90A SOD1 mutation, 87% of familial ALS in Finland is now explained by a simple monogenic cause. The repeat expansion is also present in one-third of familial ALS cases of outbred European descent, making it the most common genetic cause of these fatal neurodegenerative diseases identified to date.

Publication types

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

MeSH terms

  • Alleles
  • Amyotrophic Lateral Sclerosis / genetics*
  • Chromosomes, Human, Pair 9*
  • Female
  • Finland
  • Frontotemporal Dementia / genetics*
  • Genetic Predisposition to Disease
  • Genotype
  • Haplotypes
  • Humans
  • Male
  • Microsatellite Repeats*
  • Pedigree
  • Polymorphism, Single Nucleotide