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

Elisa Majounie, Alan E. Renton, Kin Mok, Elise G P Dopper, Adrian Waite, Sara Rollinson, Adriano Chiò, Gabriella Restagno, Nayia Nicolaou, Javier Simon-Sanchez, John C. Van Swieten, Yevgeniya Abramzon, Janel O. Johnson, Michael Sendtner, Roger Pamphlett, Richard W. Orrell, Simon Mead, Katie C. Sidle, Henry Houlden, Jonathan D. RohrerKaren E. Morrison, Hardev Pall, Kevin Talbot, Olaf Ansorge, Dena G. Hernandez, Sampath Arepalli, Mario Sabatelli, Gabriele Mora, Massimo Corbo, Fabio Giannini, Andrea Calvo, Elisabet Englund, Giuseppe Borghero, Gian Luca Floris, Anne M. Remes, Hannu Laaksovirta, Leo McCluskey, John Q. Trojanowski, Vivianna M. Van Deerlin, Gerard D. Schellenberg, Michael A. Nalls, Vivian E. Drory, Chin Song Lu, Tu Hsueh Yeh, Hiroyuki Ishiura, Yuji Takahashi, Shoji Tsuji, Isabelle Le Ber, Alexis Brice, Carsten Drepper, Nigel Leader-Williams, Janine Kirby, Pamela Shaw, John Hardy, Pentti J. Tienari, Peter Heutink, Huw R. Morris, Stuart Pickering-Brown, Bryan J. Traynor

Research output: Contribution to journalArticle

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Abstract

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).

Original languageEnglish
Pages (from-to)323-330
Number of pages8
JournalThe Lancet Neurology
Volume11
Issue number4
DOIs
Publication statusPublished - Apr 2012
Externally publishedYes

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Amyotrophic Lateral Sclerosis
Cross-Sectional Studies
Frontotemporal Dementia
Haplotypes
Mutation
Neurodegenerative Diseases
Pacific Islands
North American Indians
Penetrance
Genetic Counseling
Hispanic Americans
Ethnic Groups
Dementia
Amyotrophic lateral sclerosis 1
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia : A cross-sectional study. / Majounie, Elisa; Renton, Alan E.; Mok, Kin; Dopper, Elise G P; Waite, Adrian; Rollinson, Sara; Chiò, Adriano; Restagno, Gabriella; Nicolaou, Nayia; Simon-Sanchez, Javier; Van Swieten, John C.; Abramzon, Yevgeniya; Johnson, Janel O.; Sendtner, Michael; Pamphlett, Roger; Orrell, Richard W.; Mead, Simon; Sidle, Katie C.; Houlden, Henry; Rohrer, Jonathan D.; Morrison, Karen E.; Pall, Hardev; Talbot, Kevin; Ansorge, Olaf; Hernandez, Dena G.; Arepalli, Sampath; Sabatelli, Mario; Mora, Gabriele; Corbo, Massimo; Giannini, Fabio; Calvo, Andrea; Englund, Elisabet; Borghero, Giuseppe; Floris, Gian Luca; Remes, Anne M.; Laaksovirta, Hannu; McCluskey, Leo; Trojanowski, John Q.; Van Deerlin, Vivianna M.; Schellenberg, Gerard D.; Nalls, Michael A.; Drory, Vivian E.; Lu, Chin Song; Yeh, Tu Hsueh; Ishiura, Hiroyuki; Takahashi, Yuji; Tsuji, Shoji; Le Ber, Isabelle; Brice, Alexis; Drepper, Carsten; Leader-Williams, Nigel; Kirby, Janine; Shaw, Pamela; Hardy, John; Tienari, Pentti J.; Heutink, Peter; Morris, Huw R.; Pickering-Brown, Stuart; Traynor, Bryan J.

In: The Lancet Neurology, Vol. 11, No. 4, 04.2012, p. 323-330.

Research output: Contribution to journalArticle

Majounie, E, Renton, AE, Mok, K, Dopper, EGP, Waite, A, Rollinson, S, Chiò, A, Restagno, G, Nicolaou, N, Simon-Sanchez, J, Van Swieten, JC, Abramzon, Y, Johnson, JO, Sendtner, M, Pamphlett, R, Orrell, RW, Mead, S, Sidle, KC, Houlden, H, Rohrer, JD, Morrison, KE, Pall, H, Talbot, K, Ansorge, O, Hernandez, DG, Arepalli, S, Sabatelli, M, Mora, G, Corbo, M, Giannini, F, Calvo, A, Englund, E, Borghero, G, Floris, GL, Remes, AM, Laaksovirta, H, McCluskey, L, Trojanowski, JQ, Van Deerlin, VM, Schellenberg, GD, Nalls, MA, Drory, VE, Lu, CS, Yeh, TH, Ishiura, H, Takahashi, Y, Tsuji, S, Le Ber, I, Brice, A, Drepper, C, Leader-Williams, N, Kirby, J, Shaw, P, Hardy, J, Tienari, PJ, Heutink, P, Morris, HR, Pickering-Brown, S & Traynor, BJ 2012, 'Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: A cross-sectional study', The Lancet Neurology, vol. 11, no. 4, pp. 323-330. https://doi.org/10.1016/S1474-4422(12)70043-1
Majounie, Elisa ; Renton, Alan E. ; Mok, Kin ; Dopper, Elise G P ; Waite, Adrian ; Rollinson, Sara ; Chiò, Adriano ; Restagno, Gabriella ; Nicolaou, Nayia ; Simon-Sanchez, Javier ; Van Swieten, John C. ; Abramzon, Yevgeniya ; Johnson, Janel O. ; Sendtner, Michael ; Pamphlett, Roger ; Orrell, Richard W. ; Mead, Simon ; Sidle, Katie C. ; Houlden, Henry ; Rohrer, Jonathan D. ; Morrison, Karen E. ; Pall, Hardev ; Talbot, Kevin ; Ansorge, Olaf ; Hernandez, Dena G. ; Arepalli, Sampath ; Sabatelli, Mario ; Mora, Gabriele ; Corbo, Massimo ; Giannini, Fabio ; Calvo, Andrea ; Englund, Elisabet ; Borghero, Giuseppe ; Floris, Gian Luca ; Remes, Anne M. ; Laaksovirta, Hannu ; McCluskey, Leo ; Trojanowski, John Q. ; Van Deerlin, Vivianna M. ; Schellenberg, Gerard D. ; Nalls, Michael A. ; Drory, Vivian E. ; Lu, Chin Song ; Yeh, Tu Hsueh ; Ishiura, Hiroyuki ; Takahashi, Yuji ; Tsuji, Shoji ; Le Ber, Isabelle ; Brice, Alexis ; Drepper, Carsten ; Leader-Williams, Nigel ; Kirby, Janine ; Shaw, Pamela ; Hardy, John ; Tienari, Pentti J. ; Heutink, Peter ; Morris, Huw R. ; Pickering-Brown, Stuart ; Traynor, Bryan J. / Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia : A cross-sectional study. In: The Lancet Neurology. 2012 ; Vol. 11, No. 4. pp. 323-330.
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title = "Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: A cross-sectional study",
abstract = "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).",
author = "Elisa Majounie and Renton, {Alan E.} and Kin Mok and Dopper, {Elise G P} and Adrian Waite and Sara Rollinson and Adriano Chi{\`o} and Gabriella Restagno and Nayia Nicolaou and Javier Simon-Sanchez and {Van Swieten}, {John C.} and Yevgeniya Abramzon and Johnson, {Janel O.} and Michael Sendtner and Roger Pamphlett and Orrell, {Richard W.} and Simon Mead and Sidle, {Katie C.} and Henry Houlden and Rohrer, {Jonathan D.} and Morrison, {Karen E.} and Hardev Pall and Kevin Talbot and Olaf Ansorge and Hernandez, {Dena G.} and Sampath Arepalli and Mario Sabatelli and Gabriele Mora and Massimo Corbo and Fabio Giannini and Andrea Calvo and Elisabet Englund and Giuseppe Borghero and Floris, {Gian Luca} and Remes, {Anne M.} and Hannu Laaksovirta and Leo McCluskey and Trojanowski, {John Q.} and {Van Deerlin}, {Vivianna M.} and Schellenberg, {Gerard D.} and Nalls, {Michael A.} and Drory, {Vivian E.} and Lu, {Chin Song} and Yeh, {Tu Hsueh} and Hiroyuki Ishiura and Yuji Takahashi and Shoji Tsuji and {Le Ber}, Isabelle and Alexis Brice and Carsten Drepper and Nigel Leader-Williams and Janine Kirby and Pamela Shaw and John Hardy and Tienari, {Pentti J.} and Peter Heutink and Morris, {Huw R.} and Stuart Pickering-Brown and Traynor, {Bryan J.}",
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TY - JOUR

T1 - Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia

T2 - A cross-sectional study

AU - Majounie, Elisa

AU - Renton, Alan E.

AU - Mok, Kin

AU - Dopper, Elise G P

AU - Waite, Adrian

AU - Rollinson, Sara

AU - Chiò, Adriano

AU - Restagno, Gabriella

AU - Nicolaou, Nayia

AU - Simon-Sanchez, Javier

AU - Van Swieten, John C.

AU - Abramzon, Yevgeniya

AU - Johnson, Janel O.

AU - Sendtner, Michael

AU - Pamphlett, Roger

AU - Orrell, Richard W.

AU - Mead, Simon

AU - Sidle, Katie C.

AU - Houlden, Henry

AU - Rohrer, Jonathan D.

AU - Morrison, Karen E.

AU - Pall, Hardev

AU - Talbot, Kevin

AU - Ansorge, Olaf

AU - Hernandez, Dena G.

AU - Arepalli, Sampath

AU - Sabatelli, Mario

AU - Mora, Gabriele

AU - Corbo, Massimo

AU - Giannini, Fabio

AU - Calvo, Andrea

AU - Englund, Elisabet

AU - Borghero, Giuseppe

AU - Floris, Gian Luca

AU - Remes, Anne M.

AU - Laaksovirta, Hannu

AU - McCluskey, Leo

AU - Trojanowski, John Q.

AU - Van Deerlin, Vivianna M.

AU - Schellenberg, Gerard D.

AU - Nalls, Michael A.

AU - Drory, Vivian E.

AU - Lu, Chin Song

AU - Yeh, Tu Hsueh

AU - Ishiura, Hiroyuki

AU - Takahashi, Yuji

AU - Tsuji, Shoji

AU - Le Ber, Isabelle

AU - Brice, Alexis

AU - Drepper, Carsten

AU - Leader-Williams, Nigel

AU - Kirby, Janine

AU - Shaw, Pamela

AU - Hardy, John

AU - Tienari, Pentti J.

AU - Heutink, Peter

AU - Morris, Huw R.

AU - Pickering-Brown, Stuart

AU - Traynor, Bryan J.

PY - 2012/4

Y1 - 2012/4

N2 - 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).

AB - 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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