Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study


BACKGROUND We aimed to accurately estimate the frequency of a hexanucleotide repeat expansion in C9orf72 that has been associated with a large proportion of cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). METHODS We screened 4448 patients diagnosed with ALS (El Escorial criteria) and 1425 patients with FTD (Lund-Manchester criteria) from 17 regions worldwide for the GGGGCC hexanucleotide expansion using a repeat-primed PCR assay. We assessed familial disease status on the basis of self-reported family history of similar neurodegenerative diseases at the time of sample collection. We compared haplotype data for 262 patients carrying the expansion with the known Finnish founder risk haplotype across the chromosomal locus. We calculated age-related penetrance using the Kaplan-Meier method with data for 603 individuals with the expansion. FINDINGS In patients with sporadic ALS, we identified the repeat expansion in 236 (7·0%) of 3377 white individuals from the USA, Europe, and Australia, two (4·1%) of 49 black individuals from the USA, and six (8·3%) of 72 Hispanic individuals from the USA. The mutation was present in 217 (39·3%) of 552 white individuals with familial ALS from Europe and the USA. 59 (6·0%) of 981 white Europeans with sporadic FTD had the mutation, as did 99 (24·8%) of 400 white Europeans with familial FTD. Data for other ethnic groups were sparse, but we identified one Asian patient with familial ALS (from 20 assessed) and two with familial FTD (from three assessed) who carried the mutation. The mutation was not carried by the three Native Americans or 360 patients from Asia or the Pacific Islands with sporadic ALS who were tested, or by 41 Asian patients with sporadic FTD. All patients with the repeat expansion had (partly or fully) the founder haplotype, suggesting a one-off expansion occurring about 1500 years ago. The pathogenic expansion was non-penetrant in individuals younger than 35 years, 50% penetrant by 58 years, and almost fully penetrant by 80 years. INTERPRETATION A common Mendelian genetic lesion in C9orf72 is implicated in many cases of sporadic and familial ALS and FTD. Testing for this pathogenic expansion should be considered in the management and genetic counselling of patients with these fatal neurodegenerative diseases. FUNDING Full funding sources listed at end of paper (see Acknowledgments).

DOI: 10.1016/S1474-4422(12)70043-1

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@inproceedings{Majounie2012FrequencyOT, title={Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study}, author={Elisa Majounie and Alan E.M. Renton and Kin Y. Mok and Elise GP Dopper and Adrian J Waite and Sara J Rollinson and Adriano Chi{\`o} and Gabriella Restagno and Nayia Nicolaou and Javier Sim{\'o}n-S{\'a}nchez and John Cornelis van Swieten and Yevgeniya A Abramzon and Janel O. Johnson and Michael Sendtner and Roger Pamphlett and Richard W. Orrell and Simon Mead and Katie Claire Louise Sidle and Henry Houlden and Jonathan D. Rohrer and Karen E. Morrison and Hardev Singh Pall and Kevin Talbot and Olaf Ansorge and Dena G. Hernandez and Sampath K Arepalli and Mario Sabatelli and Gabriele Mora and Massimo Corbo and F. Giannini and Andrea Calvo and Elisabet Englund and Giuseppe Borghero and Gian Luca Floris and Anne Marja Remes and Hannu Laaksovirta and L. F. McCluskey and John Q. Trojanowski and Vivianna M Van Deerlin and Gerard D. Schellenberg and Michael A. Nalls and Vivian Drory and Chin-Song Lu and Tu-Hsueh Yeh and Hiroyuki Ishiura and Yuji Takahashi and Shoji Tsuji and Isabelle le Ber and Alexis Brice and Carsten Drepper and Nigel Williams and Janine Kirby and Pamela J Shaw and John Hardy and Pentti J. Tienari and Peter Heutink and Huw R Morris and Stuart M. Pickering-Brown and Bryan J. Traynor}, booktitle={The Lancet Neurology}, year={2012} }