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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
Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
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2017 (English)In: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, ISSN 2167-8421, E-ISSN 2167-9223, Vol. 18, no 3-4, 256-264 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2017. Vol. 18, no 3-4, 256-264 p.
Keyword [en]
ALS, C9orf72, FTD, RP-PCR interpretation, variants
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:umu:diva-134981DOI: 10.1080/21678421.2016.1262423PubMedID: 27936955OAI: oai:DiVA.org:umu-134981DiVA: diva2:1095579
Available from: 2017-05-15 Created: 2017-05-15 Last updated: 2017-05-16Bibliographically approved

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Nordin, AngelicaAlstermark, HelenaForsberg, KarinNordin, FridaBrännström, ThomasAndersen, Peter M.
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Clinical NeuroscienceDepartment of ChemistryDepartment of Medical Biosciences
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Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
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CiteExportLink to record
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