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Sequence variations in C9orf72 downstream of the hexanucleotide repeat region and its effect on repeat-primed PCR interpretation: a large multinational screening study.
Journal article

Sequence variations in C9orf72 downstream of the hexanucleotide repeat region and its effect on repeat-primed PCR interpretation: a large multinational screening study.

  • Nordin A a Department of Pharmacology and Clinical Neuroscience , Umeå University , Umeå , Sweden.
  • Akimoto C b Division of Neurology, Department of Internal Medicine , Jichi Medical University , Tochigi , Japan.
  • Wuolikainen A c Department of Chemistry , Umeå University , Umeå , Sweden.
  • Alstermark H a Department of Pharmacology and Clinical Neuroscience , Umeå University , Umeå , Sweden.
  • Forsberg K e Department of Medical Biosciences , Umeå University , Umeå , Sweden.
  • Baumann P f Department of Neurology , Central Hospital of Lapland , Rovaniemi , Finland.
  • Pinto S g Institute of Physiology and Institute of Molecular Medicine , University of Lisbon , Lisbon , Portugal.
  • de Carvalho M g Institute of Physiology and Institute of Molecular Medicine , University of Lisbon , Lisbon , Portugal.
  • Hübers A i Department of Neurology , Ulm University , Ulm , Germany.
  • Nordin F a Department of Pharmacology and Clinical Neuroscience , Umeå University , Umeå , Sweden.
  • Ludolph AC i Department of Neurology , Ulm University , Ulm , Germany.
  • Weishaupt JH i Department of Neurology , Ulm University , Ulm , Germany.
  • Meyer T j Outpatient Department for ALS and other Motor Neuron Diseases , Charité-Universitätsmedizin Berlin , Berlin , Germany.
  • Grehl T k Universitätsklinik Bochum , Bochum , Germany.
  • Schweikert K l Department of Neurology , Neuromuscular Center, Basel University Hospital, University Basel , Basel , Switzerland.
  • Weber M m Kantonsspital St. Gallen , Neuromuscular Disease Centre/ALS Clinic , Switzerland.
  • Burkhardt C m Kantonsspital St. Gallen , Neuromuscular Disease Centre/ALS Clinic , Switzerland.
  • Neuwirth C m Kantonsspital St. Gallen , Neuromuscular Disease Centre/ALS Clinic , Switzerland.
  • Holmøy T n Department of Neurology , Akershus University Hospital , Lørenskog , Norway.
  • Morita M b Division of Neurology, Department of Internal Medicine , Jichi Medical University , Tochigi , Japan.
  • Tysnes OB p Department of Neurology , Haukeland University Hospital , Bergen , Norway.
  • Benatar M r Department of Neurology , University of Miami , Miami , FL , USA.
  • Wuu J r Department of Neurology , University of Miami , Miami , FL , USA.
  • Lange DJ s Department of Neurology , Hospital for Special Surgery , New York , USA.
  • Bisgård C u Department of Neurology , Lillebælt Hospital , Vejle , Denmark.
  • Asgari N u Department of Neurology , Lillebælt Hospital , Vejle , Denmark.
  • Tarvainen I w Department of Neurology , Mikkeli Central Hospital , Finland.
  • Brännström T e Department of Medical Biosciences , Umeå University , Umeå , Sweden.
  • Andersen PM a Department of Pharmacology and Clinical Neuroscience , Umeå University , Umeå , Sweden.
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  • 2016-12-13
Published in:
  • Amyotrophic lateral sclerosis & frontotemporal degeneration. - 2017
ALS
C9orf72
FTD
RP-PCR interpretation
variants
Adolescent
Adult
Age of Onset
Aged
Aged, 80 and over
Amyotrophic Lateral Sclerosis
Base Sequence
C9orf72 Protein
Cohort Studies
DNA Repeat Expansion
Female
Frontotemporal Dementia
Gene Frequency
Genetic Predisposition to Disease
Genetic Variation
Humans
Male
Middle Aged
Polymerase Chain Reaction
Survival Analysis
Young Adult
English A large GGGGCC-repeat expansion mutation (HREM) in C9orf72 is the most common known cause of ALS and FTD in European populations. Sequence variations immediately downstream of the HREM region have previously been observed and have been suggested to be one reason for difficulties in interpreting RP-PCR data. Our objective was to determine the properties of these sequence variations with regard to prevalence, the range of variation, and effect on disease prognosis. We screened a multi-national cohort (n = 6981) for the HREM and samples with deviant RP-PCR curves were identified. The deviant samples were subsequently sequenced to determine sequence alteration. Our results show that in the USA and European cohorts (n = 6508) 10.7% carried the HREM and 3% had a sequence variant, while no HREM or sequence variants were observed in the Japanese cohort (n = 473). Sequence variations were more common on HREM alleles; however, certain population specific variants were associated with a non-expanded allele.In conclusion, we identified 38 different sequence variants, most located within the first 50 bp downstream of the HREM region. Furthermore, the presence of an HREM was found to be coupled to a lower age of onset and a shorter disease survival, while sequence variation did not have any correlation with these parameters.
Language
  • English
Open access status
closed
Identifiers
Persistent URL
https://susi.usi.ch/global/documents/202036
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