Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study - 20/03/12

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

Elisa Majounie, PhD ^a,^{^{*
Authors contributed equally}}, Alan E Renton, PhD ^b,^{^{*
Authors contributed equally}}, Kin Mok, MSc ^c,^{^{*
Authors contributed equally}}, Elise GP Dopper ^h,^i,^{^{*
Authors contributed equally}}, Adrian Waite, PhD ^j,^{^{*
Authors contributed equally}}, Sara Rollinson, PhD ^k,^{^{*
Authors contributed equally}}, Adriano Chiò, MD ^l,^{^{*
Authors contributed equally}}, Gabriella Restagno, MD ^m,^{^{*
Authors contributed equally}}, Nayia Nicolaou, MSc ^h,^i,^{^{*
Authors contributed equally}}, Javier Simon-Sanchez, PhD ^h,^i,^{^{*
Authors contributed equally}}, John C van Swieten, ProfMD ^h,^i,^{^{*
Authors contributed equally}}, Yevgeniya Abramzon ^b, Janel O Johnson, PhD ^b, Michael Sendtner, ProfMD ⁿ, Roger Pamphlett, MD ^o, Richard W Orrell, MD ^d, Simon Mead, MD ^e, Katie C Sidle, MD ^c, Henry Houlden, ProfMD ^f, Jonathan D Rohrer, MD ^g, Karen E Morrison, ProfMD ^p, Hardev Pall, MD ^q, Kevin Talbot, ProfMD ^r, Olaf Ansorge, MD ^r,
The Chromosome 9-ALS/FTD Consortium^{^†}
Members listed in the appendix
The French research network on FTLD/FTLD/ALS^{^†}
Members listed in the appendix
The ITALSGEN Consortium^{^†}
Members listed in the appendix
Dena G Hernandez, MSc ^a, Sampath Arepalli, MS ^a, Mario Sabatelli, MD ^s, Gabriele Mora, MD ^t, Massimo Corbo, MD ^u, Fabio Giannini, MD ^v, Andrea Calvo, MD ^l, Elisabet Englund, MD ^w, Giuseppe Borghero, MD ^x, Gian Luca Floris, MD ^x, Anne M Remes, ProfMD ^y, Hannu Laaksovirta, MD ^z, Leo McCluskey, MD ^aa, John Q Trojanowski, ProfMD ^ab, Vivianna M Van Deerlin, MD ^ab, Gerard D Schellenberg, ProfPhD ^ab, Michael A Nalls, PhD ^a, Vivian E Drory, MD ^ac, Chin-Song Lu, ProfMD ^ad,^ae, Tu-Hsueh Yeh, MD ^ad,^ae, Hiroyuki Ishiura, MD ^af, Yuji Takahashi, MD ^af, Shoji Tsuji, ProfMD ^af, Isabelle Le Ber, MD ^ag,^ah,^ai, Alexis Brice, ProfMD ^ag,^ah,^ai, Carsten Drepper, PhD ⁿ, Nigel Williams, PhD ^j, Janine Kirby, PhD ^aj, Pamela Shaw, ProfMD ^aj, John Hardy, ProfPhD ^c, Pentti J Tienari, MD ^z,^{^{*
Authors contributed equally}}, Peter Heutink, ProfPhD ^h,^{^{*
Authors contributed equally}}, Huw R Morris, MD ^j,^ak,^al,^{^{*
Authors contributed equally}}, Stuart Pickering-Brown, ProfPhD ^k,^{^{*
Authors contributed equally}}, Bryan J Traynor, DrMD ^b,^am,^{^{*
Authors contributed equally}}^⁎
^a Molecular Genetics Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA
^b Neuromuscular Diseases Research Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA
^c Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, University College London, Queen Square House, London, UK
^d Department of Clinical Neurosciences, Institute of Neurology, University College London, Queen Square House, London, UK
^e MRC Prion Unit, Department of Neurodegenerative Disease, Institute of Neurology, University College London, Queen Square House, London, UK
^f Department of Molecular Neurosciences and MRC Centre for Neuromuscular Diseases, Institute of Neurology, University College London, Queen Square House, London, UK
^g Department of Neurodegenerative Disease, Dementia Research Centre, Institute of Neurology, University College London, Queen Square House, London, UK
^h Department of Clinical Genetics, Section of Medical Genomics, and Alzheimer Center, VU University Medical Centre, Amsterdam, Netherlands
ⁱ Department of Neurology, Erasmus MC–University Medical Center Rotterdam, Rotterdam, Netherlands
^j MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, UK
^k Faculty of Human and Medical Sciences, University of Manchester, Manchester, UK
^l Department of Neuroscience, University of Turin, Turin, Italy
^m Molecular Genetics Unit, Department of Clinical Pathology, Azienda Ospedaliera Ospedale Infantile Regina Margherita Sant Anna, Turin, Italy
ⁿ Institute for Clinical Neurobiology, University of Würzburg, Würzburg, Germany
^o Department of Pathology, Sydney Medical School, The University of Sydney, NSW, Australia
^p Department of Neurology, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
^q Neurology–University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Queen Elizabeth Medical Centre, Birmingham, UK
^r Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, UK
^s Neurological Institute, Catholic University and ICOMM Association for ALS Research, Rome, Italy
^t ALS Center, Salvatore Maugeri Foundation, Milan, Italy
^u NeuroMuscular Omnicentre, Niguarda Ca’ Granda Hospital, Milan, Italy
^v Department of Neurological, Neurosurgical and Behavioural Sciences, Neurology Section, University of Siena, Siena, Italy
^w Department of Pathology, Lund University, Regional Laboratories Region Skåne, Lund, Sweden
^x Department of Neurology, Azienda Universitaria-Ospedaliera di Cagliari and University of Cagliari, Cagliari, Italy
^y Institute of Clinical Medicine, Neurology, University of Oulu and Clinical Research Center, Oulu University Hospital, Oulu, Finland
^z Department of Neurology, Helsinki University Central Hospital and Molecular Neurology Programme, Biomedicum, University of Helsinki, Helsinki, Finland
^aa Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA
^ab Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA
^ac Department of Neurology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel
^ad Department of Neurology, Chang Gung Memorial Hospital at Linkou Medical Center and Chang Gung University, Taoyuan, Taiwan
^ae Neuroscience Research Center, Chang Gung Memorial Hospital at Linkou Medical Center, Taoyuan, Taiwan
^af Department of Neurology, University of Tokyo Hospital, 7–3-1 Hongo, Bunkyo-ku, Tokyo, Japan
^ag Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l’Institut du Cerveau et de la Moelle épinière, Paris, France
^ah INSERM, U975, Paris, France
^ai CNRS, UMR 7225, Paris, France
^aj Department of Neuroscience, University of Sheffield, Sheffield, UK
^ak Neurology (C4), University Hospital of Wales, Cardiff, UK
^al Department of Neurology, Royal Gwent Hospital, Aneurin Bevan Local Health Board, Gwent, UK
^am Department of Neurology, Brain Sciences Institute, Johns Hopkins Hospital, Baltimore, MD, USA

^*Correspondence to: Dr Bryan J Traynor, Neuromuscular Diseases Research Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, 35 Convent Drive, Room 1A-1000, Bethesda, MD 20892, USA

Summary

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).

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Vol 11 - N° 4

P. 323-330 - avril 2012 Retour au numéro

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Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study - 20/03/12

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