Evidence map›Paper›PMID 24706941›Full record

ArticleJournal of medical genetics2014

A blinded international study on the reliability of genetic testing for GGGGCC-repeat expansions in C9orf72 reveals marked differences in results among 14 laboratories.

Chizuru Akimoto, Alexander E Volk, Marka van Blitterswijk, Marleen Van den Broeck, Claire S Leblond, Serge Lumbroso, William Camu, Birgit Neitzel, Osamu Onodera, Wouter van Rheenen and 33 more

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Article in Journal of medical genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 67 papers, 2 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
67citing papers in PubMed, 2 pooled it
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

67 citing papers in PubMed, 2 syntheses or guidelines pooled it.

  1. Frontiers in genetics · 2020
    Pooled it
  2. Pooled it
  3. Trial
  4. Article
  5. Article
  6. Article
  7. Review
  8. Review
  9. NAR molecular medicine · 2024
    Article
  10. Article
  11. Article
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  13. Article
  14. Distribution of theFrontiers in neurology · 2024
    Article
  15. Article
  16. Evidence-based consensus guidelines for ALS genetic testing and counseling.Annals of clinical and translational neurology · 2023
    Article
  17. Article
  18. Article
  19. Article
  20. Expanding Clinical Spectrum ofNeurology. Genetics · 2022
    Review

7 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

43 authors.

Chizuru AkimotoDepartment of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.
Alexander E VolkInstitute of Human Genetics, Ulm University, Ulm, Germany.
Marka van BlitterswijkDepartment of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
Marleen Van den BroeckNeurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, University of Antwerp-CDE, Antwerp, Belgium Diagnostic Service Facility, Laboratory of neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
Claire S LeblondDepartment of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.
Serge LumbrosoDepartment of Biochemistry, Nimes University Hospital, Nimes Cedex 9, France.
William CamuCenter SLA, Montpellier University Hospital, Hôpital Gui-de-Chauliac, Montpellier Cedex 5, France.
Birgit NeitzelMedizinisch Genetisches Zentrum, München, Germany.
Osamu OnoderaDepartment of Neurology, Brain Research Institute, Niigata University,  Niigata, Japan.
Wouter van RheenenDepartment of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
Susana PintoFaculty of Medicine-University of Lisbon, Instituto de Medicina Molecular, Hospital de Santa Maria, University of Lisbon, Alameda Universidade, Lisbon, Portugal.
Markus WeberDepartment of neurology, Kantonsspital St. Gallen and University Hospital, St. Gallen, Switzerland.
Bradley SmithInstitute of Psychiatry, King's College London and King's Health Partners, London, UK.
Melanie ProvenOxford Medical Genetics Laboratories, Churchill Hospital, Oxford, England.
Kevin TalbotNuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe hospital, Oxford, UK.
Pamela KeagleDepartment of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Alessandra ChesiDepartment of Genetics, Stanford University School of Medicine, Stanford, California, USA.
Antonia RattiDepartment of Pathophysiology and Transplantation, "Dino Ferrari" Center, Universtà degli Studi di Milano, Milan, Italy Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, , Milan, Italy.
Julie van der ZeeNeurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, University of Antwerp-CDE, Antwerp, Belgium Diagnostic Service Facility, Laboratory of neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
Helena AlstermarkDepartment of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.
Anna BirveDepartment of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.
Daniela CaliniDepartment of Pathophysiology and Transplantation, "Dino Ferrari" Center, Universtà degli Studi di Milano, Milan, Italy Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, , Milan, Italy.
Angelica NordinDepartment of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.
Daniela C TradowskyInstitute of Human Genetics, Ulm University, Ulm, Germany.
Walter JustInstitute of Human Genetics, Ulm University, Ulm, Germany.
Hussein DaoudDepartment of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.
Sabrina AngerbauerMedizinisch Genetisches Zentrum, München, Germany.
Mariely DeJesus-HernandezDepartment of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
Takuya KonnoDepartment of Neurology, Brain Research Institute, Niigata University,  Niigata, Japan.
Anjali Lloyd-JaniOxford Medical Genetics Laboratories, Churchill Hospital, Oxford, England.
Mamede de CarvalhoFaculty of Medicine-University of Lisbon, Instituto de Medicina Molecular, Hospital de Santa Maria, University of Lisbon, Alameda Universidade, Lisbon, Portugal.
Kevin MouzatDepartment of Biochemistry, Nimes University Hospital, Nimes Cedex 9, France.
John E LandersDepartment of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Jan H VeldinkDepartment of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
Vincenzo SilaniDepartment of Pathophysiology and Transplantation, "Dino Ferrari" Center, Universtà degli Studi di Milano, Milan, Italy Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, , Milan, Italy.
Aaron D GitlerDepartment of Genetics, Stanford University School of Medicine, Stanford, California, USA.
Christopher E ShawInstitute of Psychiatry, King's College London and King's Health Partners, London, UK.
Guy A RouleauDepartment of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.
Leonard H van den BergDepartment of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
Christine Van BroeckhovenNeurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, University of Antwerp-CDE, Antwerp, Belgium Diagnostic Service Facility, Laboratory of neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
Rosa RademakersDepartment of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden Institute of Human Genetics, Ulm University, Ulm, Germany Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, University of Antwerp-CDE, Antwerp, Belgium Diagnostic Service Facility, Laboratory of neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada Department of Biochemistry, Nimes University Hospital, Nimes Cedex 9, France Center SLA, Montpellier University Hospital, Hôpital Gui-de-Chauliac, Montpellier Cedex 5, France Medizinisch Genetisches Zentrum, München, Germany Department of Neurology, Brain Research Institute, Niigata University,  Niigata, Japan Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands Faculty of Medicine-University of Lisbon, Instituto de Medicina Molecular, Hospital de Santa Maria, University of Lisbon, Alameda Universidade, Lisbon, Portugal Department of neurology, Kantonsspital St. Gallen and University Hospital, St. Gallen, Switzerland Institute of Psychiatry, King's College London and King's Health Partners, London, UK Oxford Medical Genetics Laboratories, Churchill Hospital, Oxford, England Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe hospital, Oxford, UK Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA Department of Genetics, Stanford University School of Medicine, Stanford, California, USA Department of Pathophysiology and Transplantation, "Dino Ferrari" Center, Universtà degli Studi di Milano, Milan, Italy Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, , Milan, Italy Department of Neurology, University of Ulm,
Peter M AndersenDepartment of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden Department of Neurology, University of Ulm, Ulm, Germany.
Christian KubischInstitute of Human Genetics, Ulm University, Ulm, Germany.

Funding

Molecular Basis of TDP-43 Proteinopathies: Disease Models and MechanismsR01NS065317 · NINDS · UNIVERSITY OF PENNSYLVANIA · PI GITLER, AARON D. · 2009 to 2016
$2.7M
Ataxin-2 as a genetic risk factor for ALS: New insights into neurodegenerationR01NS073660 · NINDS · UNIVERSITY OF PENNSYLVANIA · PI BONINI, NANCY M, GITLER, AARON D. · 2011 to 2015
$1.7M
Medical Research Council G0500289Medical Research Council G0501573Medical Research Council G0600974Medical Research Council G0900635Medical Research Council G0900688Medical Research Council G1100695Medical Research Council MC_G1000733Medical Research Council MR/L501529/1NINDS NIH HHS R01 NS065317NINDS NIH HHS R01 NS073660Wellcome Trust 089701
6 · The paper itself

Abstract

backgroundThe GGGGCC-repeat expansion in C9orf72 is the most frequent mutation found in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Most of the studies on C9orf72 have relied on repeat-primed PCR (RP-PCR) methods for detection of the expansions. To investigate the inherent limitations of this technique, we compared methods and results of 14 laboratories.

methodsThe 14 laboratories genotyped DNA from 78 individuals (diagnosed with ALS or FTD) in a blinded fashion. Eleven laboratories used a combination of amplicon-length analysis and RP-PCR, whereas three laboratories used RP-PCR alone; Southern blotting techniques were used as a reference.

resultsUsing PCR-based techniques, 5 of the 14 laboratories got results in full accordance with the Southern blotting results. Only 50 of the 78 DNA samples got the same genotype result in all 14 laboratories. There was a high degree of false positive and false negative results, and at least one sample could not be genotyped at all in 9 of the 14 laboratories. The mean sensitivity of a combination of amplicon-length analysis and RP-PCR was 95.0% (73.9-100%), and the mean specificity was 98.0% (87.5-100%). Overall, a sensitivity and specificity of more than 95% was observed in only seven laboratories.

conclusionsBecause of the wide range seen in genotyping results, we recommend using a combination of amplicon-length analysis and RP-PCR as a minimum in a research setting. We propose that Southern blotting techniques should be the gold standard, and be made obligatory in a clinical diagnostic setting.

Indexed as

Amyotrophic Lateral SclerosisC9orf72 ProteinClinical Laboratory ServicesFemaleFrontotemporal DementiaGenetic TestingHumansMaleProteinsReproducibility of ResultsC9orf72 ProteinC9orf72 protein, humanProteinsMolecular geneticsMotor neurone diseaseNeurology

Identifiers

PMID24706941
PMCPMC4033024

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