Neuron
Volume 72, Issue 2, 20 October 2011, Pages 257-268
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Article
A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD

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Summary

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.

Highlights

► A GGGGCC hexanucleotide repeat expansion causes chromosome 9p21 FTD/ALS ► The GGGGCC repeat expansion accounts for nearly half of familial ALS in Finland ► The GGGGCC repeat expansion accounts for more than 1/3 of familial ALS in Europe ► The repeat expansion is the most common cause of ALS and FTD identified to date

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These authors contributed equally to this work