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Springer Nature [academic journals on nature.com], European Journal of Human Genetics, 1(21), p. 102-108, 2012

DOI: 10.1038/ejhg.2012.98

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The C9ORF72 expansion mutation is a common cause of ALS+/−FTD in Europe and has a single founder

Journal article published in 2012 by Bradley N. Smith ORCID, Stephen Newhouse, Aleksey Shatunov, Caroline Vance ORCID, Simon Topp ORCID, Lauren Johnson, Jack Miller, Younbok Lee, Claire Troakes ORCID, Kirsten M. Scott, Ashley Jones, Ian Gray, Jamie Wright, Tibor Hortobágyi, Safa Al-Sarraj and other authors.
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

A massive hexanucleotide repeat expansion mutation (HREM) in C9ORF72 has recently been linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we describe the frequency, origin and stability of this mutation in ALS+/-FTD from five European cohorts (total n=1347). Single-nucleotide polymorphisms defining the risk haplotype in linked kindreds were genotyped in cases (n=434) and controls (n=856). Haplotypes were analysed using PLINK and aged using DMLE+. In a London clinic cohort, the HREM was the most common mutation in familial ALS+/-FTD: C9ORF72 29/112 (26%), SOD1 27/112 (24%), TARDBP 1/112 (1%) and FUS 4/112 (4%) and detected in 13/216 (6%) of unselected sporadic ALS cases but was rare in controls (3/856, 0.3%). HREM prevalence was high for familial ALS+/-FTD throughout Europe: Belgium 19/22 (86%), Sweden 30/41 (73%), the Netherlands 10/27 (37%) and Italy 4/20 (20%). The HREM did not affect the age at onset or survival of ALS patients. Haplotype analysis identified a common founder in all 137 HREM carriers that arose around 6300 years ago. The haplotype from which the HREM arose is intrinsically unstable with an increased number of repeats (average 8, compared with 2 for controls, P<10(-8)). We conclude that the HREM has a single founder and is the most common mutation in familial and sporadic ALS in Europe.European Journal of Human Genetics advance online publication, 13 June 2012; doi:10.1038/ejhg.2012.98.