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

Department of Clinical Neurosciences, MRC Centre for Neurodegeneration Research, Institute of Psychiatry, Kings College London, London, UK.
European journal of human genetics: EJHG (Impact Factor: 4.35). 06/2012; 21(1). DOI: 10.1038/ejhg.2012.98
Source: PubMed


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.

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Available from: Claire Troakes, Oct 03, 2015
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    • "We now know that the most common monogenic mutated gene in Caucasians with ALS is the GGGGCC hexanucleotide repeat expansion in the C9orf72 [13], [14], which is responsible for over 30% of fALS cases, and about 6.0% of sALS in Caucasian populations [7], [15], [16]. This repeat mutation arose in Northern Europe a few thousand years ago [17], and thus occurs with a much lower frequency in Asian ALS populations [18]–[20], in particular, the mutation frequency has been shown to be extremely low in Chinese, Indian, Japanese and Korean ALS patients [16], [19]–[23]. This mutation is also associated with about 25% of familial frontotemporal lobe dementia (FTLD) and about 6% sporadic FTLD [16], [24]. "
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    • "Data analysis of a 42-SNP haplotype from carriers of the expansion in Europe, USA and Australia led to the hypothesis that there was a common founder carrying the pathogenic mutation approximately 100 generations ago in Northern Europe and this expansion then spread across the world [5]. A European study using an 82-SNP haplotype suggests the expansion is much older, with the common founder arose over 251 generations ago [19]. As the disease has a late age of onset, this means it is not subject to reproductive pressure. "
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