Association between repeat sizes and clinical and pathological characteristics in carriers of C9ORF72 repeat expansions (Xpansize-72): A cross-sectional cohort study

Marka Van Blitterswijk, Mariely DeJesus-Hernandez, Ellis Niemantsverdriet, Melissa E Murray, Michael G. Heckman, Nancy N. Diehl, Patricia H. Brown, Matthew C. Baker, NiCole A. Finch, Peter O. Bauer, Geidy Serrano, Thomas G. Beach, Keith Anthony Josephs, David S Knopman, Ronald Carl Petersen, Bradley F Boeve, Neill R Graff Radford, Kevin B. Boylan, Leonard Petrucelli, Dennis W DicksonRosa V Rademakers

Research output: Contribution to journalArticle

125 Citations (Scopus)

Abstract

Background: Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9ORF72) are the most common known genetic cause of frontotemporal dementia (FTD) and motor neuron disease (MND). We assessed whether expansion size is associated with disease severity or phenotype. Methods: We did a cross-sectional Southern blot characterisation study (Xpansize-72) in a cohort of individuals with FTD, MND, both these diseases, or no clinical phenotype. All participants had GGGGCC repeat expansions in C9ORF72, and high quality DNA was available from one or more of the frontal cortex, cerebellum, or blood. We used Southern blotting techniques and densitometry to estimate the repeat size of the most abundant expansion species. We compared repeat sizes between different tissues using Wilcoxon rank sum and Wilcoxon signed rank tests, and between disease subgroups using Kruskal-Wallis rank sum tests. We assessed the association of repeat size with age at onset and age at collection using a Spearman's test of correlation, and assessed the association between repeat size and survival after disease onset using Cox proportional hazards regression models. Findings: We included 84 individuals with C9ORF72 expansions: 35 had FTD, 16 had FTD and MND, 30 had MND, and three had no clinical phenotype. We focused our analysis on three major tissue subgroups: frontal cortex (available from 41 patients [21 with FTD, 11 with FTD and MND, and nine with MND]), cerebellum (40 patients [20 with FTD, 12 with FTD and MND, and eight with MND]), and blood (47 patients [15 with FTD, nine with FTD and MND, and 23 with MND] and three carriers who had no clinical phenotype). Repeat lengths in the cerebellum were smaller (median 12·3 kb [about 1667 repeat units], IQR 11·1-14·3) than those in the frontal cortex (33·8 kb [about 5250 repeat units], 23·5-44·9; p<0·0001) and those in blood (18·6 kb [about 2717 repeat units], 13·9-28·1; p=0·0002). Within these tissues, we detected no difference in repeat length between disease subgroups (cerebellum p=0·96, frontal cortex p=0·27, blood p=0·10). In the frontal cortex of patients with FTD, repeat length correlated with age at onset (r=0·63; p=0·003) and age at sample collection (r=0·58; p=0·006); we did not detect such a correlation in samples from the cerebellum or blood. When assessing cerebellum samples from the overall cohort, survival after disease onset was 4·8 years (IQR 3·0-7·4) in the group with expansions greater than 1467 repeat units (the 25th percentile of repeat lengths) versus 7·4 years (6·3-10·9) in the group with smaller expansions (HR 3·27, 95% CI 1·34-7·95; p=0·009). Interpretation: We detected substantial variation in repeat sizes between samples from the cerebellum, frontal cortex, and blood, and longer repeat sizes in the cerebellum seem to be associated with a survival disadvantage. Our findings indicate that expansion size does affect disease severity, which-if replicated in other cohorts-could be relevant for genetic counselling. Funding: The ALS Therapy Alliance, the National Institute of Neurological Disorders and Stroke, the National Institute on Aging, the Arizona Department of Health Services, the Arizona Biomedical Research Commission, and the Michael J Fox Foundation for Parkinson's Research.

Original languageEnglish (US)
Pages (from-to)978-988
Number of pages11
JournalThe Lancet Neurology
Volume12
Issue number10
DOIs
StatePublished - Oct 2013

Fingerprint

Frontotemporal Dementia
Chromosomes, Human, Pair 9
Motor Neuron Disease
Cerebellum
Frontal Lobe
Open Reading Frames
Cohort Studies
Cross-Sectional Studies
Phenotype
Nonparametric Statistics
Southern Blotting
Age of Onset
Survival
National Institute on Aging (U.S.)
National Institute of Neurological Disorders and Stroke
Cerebellar Diseases
Densitometry
Genetic Counseling
Proportional Hazards Models
Sample Size

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Association between repeat sizes and clinical and pathological characteristics in carriers of C9ORF72 repeat expansions (Xpansize-72) : A cross-sectional cohort study. / Van Blitterswijk, Marka; DeJesus-Hernandez, Mariely; Niemantsverdriet, Ellis; Murray, Melissa E; Heckman, Michael G.; Diehl, Nancy N.; Brown, Patricia H.; Baker, Matthew C.; Finch, NiCole A.; Bauer, Peter O.; Serrano, Geidy; Beach, Thomas G.; Josephs, Keith Anthony; Knopman, David S; Petersen, Ronald Carl; Boeve, Bradley F; Graff Radford, Neill R; Boylan, Kevin B.; Petrucelli, Leonard; Dickson, Dennis W; Rademakers, Rosa V.

In: The Lancet Neurology, Vol. 12, No. 10, 10.2013, p. 978-988.

Research output: Contribution to journalArticle

Van Blitterswijk, Marka ; DeJesus-Hernandez, Mariely ; Niemantsverdriet, Ellis ; Murray, Melissa E ; Heckman, Michael G. ; Diehl, Nancy N. ; Brown, Patricia H. ; Baker, Matthew C. ; Finch, NiCole A. ; Bauer, Peter O. ; Serrano, Geidy ; Beach, Thomas G. ; Josephs, Keith Anthony ; Knopman, David S ; Petersen, Ronald Carl ; Boeve, Bradley F ; Graff Radford, Neill R ; Boylan, Kevin B. ; Petrucelli, Leonard ; Dickson, Dennis W ; Rademakers, Rosa V. / Association between repeat sizes and clinical and pathological characteristics in carriers of C9ORF72 repeat expansions (Xpansize-72) : A cross-sectional cohort study. In: The Lancet Neurology. 2013 ; Vol. 12, No. 10. pp. 978-988.
@article{fadcc33d35da4a86a17ece715e7fbd32,
title = "Association between repeat sizes and clinical and pathological characteristics in carriers of C9ORF72 repeat expansions (Xpansize-72): A cross-sectional cohort study",
abstract = "Background: Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9ORF72) are the most common known genetic cause of frontotemporal dementia (FTD) and motor neuron disease (MND). We assessed whether expansion size is associated with disease severity or phenotype. Methods: We did a cross-sectional Southern blot characterisation study (Xpansize-72) in a cohort of individuals with FTD, MND, both these diseases, or no clinical phenotype. All participants had GGGGCC repeat expansions in C9ORF72, and high quality DNA was available from one or more of the frontal cortex, cerebellum, or blood. We used Southern blotting techniques and densitometry to estimate the repeat size of the most abundant expansion species. We compared repeat sizes between different tissues using Wilcoxon rank sum and Wilcoxon signed rank tests, and between disease subgroups using Kruskal-Wallis rank sum tests. We assessed the association of repeat size with age at onset and age at collection using a Spearman's test of correlation, and assessed the association between repeat size and survival after disease onset using Cox proportional hazards regression models. Findings: We included 84 individuals with C9ORF72 expansions: 35 had FTD, 16 had FTD and MND, 30 had MND, and three had no clinical phenotype. We focused our analysis on three major tissue subgroups: frontal cortex (available from 41 patients [21 with FTD, 11 with FTD and MND, and nine with MND]), cerebellum (40 patients [20 with FTD, 12 with FTD and MND, and eight with MND]), and blood (47 patients [15 with FTD, nine with FTD and MND, and 23 with MND] and three carriers who had no clinical phenotype). Repeat lengths in the cerebellum were smaller (median 12·3 kb [about 1667 repeat units], IQR 11·1-14·3) than those in the frontal cortex (33·8 kb [about 5250 repeat units], 23·5-44·9; p<0·0001) and those in blood (18·6 kb [about 2717 repeat units], 13·9-28·1; p=0·0002). Within these tissues, we detected no difference in repeat length between disease subgroups (cerebellum p=0·96, frontal cortex p=0·27, blood p=0·10). In the frontal cortex of patients with FTD, repeat length correlated with age at onset (r=0·63; p=0·003) and age at sample collection (r=0·58; p=0·006); we did not detect such a correlation in samples from the cerebellum or blood. When assessing cerebellum samples from the overall cohort, survival after disease onset was 4·8 years (IQR 3·0-7·4) in the group with expansions greater than 1467 repeat units (the 25th percentile of repeat lengths) versus 7·4 years (6·3-10·9) in the group with smaller expansions (HR 3·27, 95{\%} CI 1·34-7·95; p=0·009). Interpretation: We detected substantial variation in repeat sizes between samples from the cerebellum, frontal cortex, and blood, and longer repeat sizes in the cerebellum seem to be associated with a survival disadvantage. Our findings indicate that expansion size does affect disease severity, which-if replicated in other cohorts-could be relevant for genetic counselling. Funding: The ALS Therapy Alliance, the National Institute of Neurological Disorders and Stroke, the National Institute on Aging, the Arizona Department of Health Services, the Arizona Biomedical Research Commission, and the Michael J Fox Foundation for Parkinson's Research.",
author = "{Van Blitterswijk}, Marka and Mariely DeJesus-Hernandez and Ellis Niemantsverdriet and Murray, {Melissa E} and Heckman, {Michael G.} and Diehl, {Nancy N.} and Brown, {Patricia H.} and Baker, {Matthew C.} and Finch, {NiCole A.} and Bauer, {Peter O.} and Geidy Serrano and Beach, {Thomas G.} and Josephs, {Keith Anthony} and Knopman, {David S} and Petersen, {Ronald Carl} and Boeve, {Bradley F} and {Graff Radford}, {Neill R} and Boylan, {Kevin B.} and Leonard Petrucelli and Dickson, {Dennis W} and Rademakers, {Rosa V}",
year = "2013",
month = "10",
doi = "10.1016/S1474-4422(13)70210-2",
language = "English (US)",
volume = "12",
pages = "978--988",
journal = "The Lancet Neurology",
issn = "1474-4422",
publisher = "Lancet Publishing Group",
number = "10",

}

TY - JOUR

T1 - Association between repeat sizes and clinical and pathological characteristics in carriers of C9ORF72 repeat expansions (Xpansize-72)

T2 - A cross-sectional cohort study

AU - Van Blitterswijk, Marka

AU - DeJesus-Hernandez, Mariely

AU - Niemantsverdriet, Ellis

AU - Murray, Melissa E

AU - Heckman, Michael G.

AU - Diehl, Nancy N.

AU - Brown, Patricia H.

AU - Baker, Matthew C.

AU - Finch, NiCole A.

AU - Bauer, Peter O.

AU - Serrano, Geidy

AU - Beach, Thomas G.

AU - Josephs, Keith Anthony

AU - Knopman, David S

AU - Petersen, Ronald Carl

AU - Boeve, Bradley F

AU - Graff Radford, Neill R

AU - Boylan, Kevin B.

AU - Petrucelli, Leonard

AU - Dickson, Dennis W

AU - Rademakers, Rosa V

PY - 2013/10

Y1 - 2013/10

N2 - Background: Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9ORF72) are the most common known genetic cause of frontotemporal dementia (FTD) and motor neuron disease (MND). We assessed whether expansion size is associated with disease severity or phenotype. Methods: We did a cross-sectional Southern blot characterisation study (Xpansize-72) in a cohort of individuals with FTD, MND, both these diseases, or no clinical phenotype. All participants had GGGGCC repeat expansions in C9ORF72, and high quality DNA was available from one or more of the frontal cortex, cerebellum, or blood. We used Southern blotting techniques and densitometry to estimate the repeat size of the most abundant expansion species. We compared repeat sizes between different tissues using Wilcoxon rank sum and Wilcoxon signed rank tests, and between disease subgroups using Kruskal-Wallis rank sum tests. We assessed the association of repeat size with age at onset and age at collection using a Spearman's test of correlation, and assessed the association between repeat size and survival after disease onset using Cox proportional hazards regression models. Findings: We included 84 individuals with C9ORF72 expansions: 35 had FTD, 16 had FTD and MND, 30 had MND, and three had no clinical phenotype. We focused our analysis on three major tissue subgroups: frontal cortex (available from 41 patients [21 with FTD, 11 with FTD and MND, and nine with MND]), cerebellum (40 patients [20 with FTD, 12 with FTD and MND, and eight with MND]), and blood (47 patients [15 with FTD, nine with FTD and MND, and 23 with MND] and three carriers who had no clinical phenotype). Repeat lengths in the cerebellum were smaller (median 12·3 kb [about 1667 repeat units], IQR 11·1-14·3) than those in the frontal cortex (33·8 kb [about 5250 repeat units], 23·5-44·9; p<0·0001) and those in blood (18·6 kb [about 2717 repeat units], 13·9-28·1; p=0·0002). Within these tissues, we detected no difference in repeat length between disease subgroups (cerebellum p=0·96, frontal cortex p=0·27, blood p=0·10). In the frontal cortex of patients with FTD, repeat length correlated with age at onset (r=0·63; p=0·003) and age at sample collection (r=0·58; p=0·006); we did not detect such a correlation in samples from the cerebellum or blood. When assessing cerebellum samples from the overall cohort, survival after disease onset was 4·8 years (IQR 3·0-7·4) in the group with expansions greater than 1467 repeat units (the 25th percentile of repeat lengths) versus 7·4 years (6·3-10·9) in the group with smaller expansions (HR 3·27, 95% CI 1·34-7·95; p=0·009). Interpretation: We detected substantial variation in repeat sizes between samples from the cerebellum, frontal cortex, and blood, and longer repeat sizes in the cerebellum seem to be associated with a survival disadvantage. Our findings indicate that expansion size does affect disease severity, which-if replicated in other cohorts-could be relevant for genetic counselling. Funding: The ALS Therapy Alliance, the National Institute of Neurological Disorders and Stroke, the National Institute on Aging, the Arizona Department of Health Services, the Arizona Biomedical Research Commission, and the Michael J Fox Foundation for Parkinson's Research.

AB - Background: Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9ORF72) are the most common known genetic cause of frontotemporal dementia (FTD) and motor neuron disease (MND). We assessed whether expansion size is associated with disease severity or phenotype. Methods: We did a cross-sectional Southern blot characterisation study (Xpansize-72) in a cohort of individuals with FTD, MND, both these diseases, or no clinical phenotype. All participants had GGGGCC repeat expansions in C9ORF72, and high quality DNA was available from one or more of the frontal cortex, cerebellum, or blood. We used Southern blotting techniques and densitometry to estimate the repeat size of the most abundant expansion species. We compared repeat sizes between different tissues using Wilcoxon rank sum and Wilcoxon signed rank tests, and between disease subgroups using Kruskal-Wallis rank sum tests. We assessed the association of repeat size with age at onset and age at collection using a Spearman's test of correlation, and assessed the association between repeat size and survival after disease onset using Cox proportional hazards regression models. Findings: We included 84 individuals with C9ORF72 expansions: 35 had FTD, 16 had FTD and MND, 30 had MND, and three had no clinical phenotype. We focused our analysis on three major tissue subgroups: frontal cortex (available from 41 patients [21 with FTD, 11 with FTD and MND, and nine with MND]), cerebellum (40 patients [20 with FTD, 12 with FTD and MND, and eight with MND]), and blood (47 patients [15 with FTD, nine with FTD and MND, and 23 with MND] and three carriers who had no clinical phenotype). Repeat lengths in the cerebellum were smaller (median 12·3 kb [about 1667 repeat units], IQR 11·1-14·3) than those in the frontal cortex (33·8 kb [about 5250 repeat units], 23·5-44·9; p<0·0001) and those in blood (18·6 kb [about 2717 repeat units], 13·9-28·1; p=0·0002). Within these tissues, we detected no difference in repeat length between disease subgroups (cerebellum p=0·96, frontal cortex p=0·27, blood p=0·10). In the frontal cortex of patients with FTD, repeat length correlated with age at onset (r=0·63; p=0·003) and age at sample collection (r=0·58; p=0·006); we did not detect such a correlation in samples from the cerebellum or blood. When assessing cerebellum samples from the overall cohort, survival after disease onset was 4·8 years (IQR 3·0-7·4) in the group with expansions greater than 1467 repeat units (the 25th percentile of repeat lengths) versus 7·4 years (6·3-10·9) in the group with smaller expansions (HR 3·27, 95% CI 1·34-7·95; p=0·009). Interpretation: We detected substantial variation in repeat sizes between samples from the cerebellum, frontal cortex, and blood, and longer repeat sizes in the cerebellum seem to be associated with a survival disadvantage. Our findings indicate that expansion size does affect disease severity, which-if replicated in other cohorts-could be relevant for genetic counselling. Funding: The ALS Therapy Alliance, the National Institute of Neurological Disorders and Stroke, the National Institute on Aging, the Arizona Department of Health Services, the Arizona Biomedical Research Commission, and the Michael J Fox Foundation for Parkinson's Research.

UR - http://www.scopus.com/inward/record.url?scp=84884163243&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84884163243&partnerID=8YFLogxK

U2 - 10.1016/S1474-4422(13)70210-2

DO - 10.1016/S1474-4422(13)70210-2

M3 - Article

C2 - 24011653

AN - SCOPUS:84884163243

VL - 12

SP - 978

EP - 988

JO - The Lancet Neurology

JF - The Lancet Neurology

SN - 1474-4422

IS - 10

ER -