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

Angelica Nordin, Chizuru Akimoto, Anna Wuolikainen, Helena Alstermark, Karin Forsberg, Peter Baumann, Susana Pinto, Mamede de Carvalho, Annemarie Hübers, Frida Nordin, Albert C. Ludolph, Jochen H. Weishaupt, Thomas Meyer, Torsten Grehl, Kathi Schweikert, Markus Weber, Christian Burkhardt, Christoph Neuwirth, Trygve Holmøy, Mitsuya MoritaOle Bjørn Tysnes, Michael G Benatar, Joanne Wuu, Dale J. Lange, Carsten Bisgård, Nasrin Asgari, Ilkka Tarvainen, Thomas Brännström, Peter M. Andersen

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1-9
Number of pages9
JournalAmyotrophic Lateral Sclerosis and Frontotemporal Degeneration
DOIs
StateAccepted/In press - Dec 6 2016

Fingerprint

Alleles
Polymerase Chain Reaction
Age of Onset
Population
Mutation

Keywords

  • ALS
  • C9orf72
  • FTD
  • RP-PCR interpretation
  • variants

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Sequence variations in C9orf72 downstream of the hexanucleotide repeat region and its effect on repeat-primed PCR interpretation : a large multinational screening study. / Nordin, Angelica; Akimoto, Chizuru; Wuolikainen, Anna; Alstermark, Helena; Forsberg, Karin; Baumann, Peter; Pinto, Susana; de Carvalho, Mamede; Hübers, Annemarie; Nordin, Frida; Ludolph, Albert C.; Weishaupt, Jochen H.; Meyer, Thomas; Grehl, Torsten; Schweikert, Kathi; Weber, Markus; Burkhardt, Christian; Neuwirth, Christoph; Holmøy, Trygve; Morita, Mitsuya; Tysnes, Ole Bjørn; Benatar, Michael G; Wuu, Joanne; Lange, Dale J.; Bisgård, Carsten; Asgari, Nasrin; Tarvainen, Ilkka; Brännström, Thomas; Andersen, Peter M.

In: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 06.12.2016, p. 1-9.

Research output: Contribution to journalArticle

Nordin, A, Akimoto, C, Wuolikainen, A, Alstermark, H, Forsberg, K, Baumann, P, Pinto, S, de Carvalho, M, Hübers, A, Nordin, F, Ludolph, AC, Weishaupt, JH, Meyer, T, Grehl, T, Schweikert, K, Weber, M, Burkhardt, C, Neuwirth, C, Holmøy, T, Morita, M, Tysnes, OB, Benatar, MG, Wuu, J, Lange, DJ, Bisgård, C, Asgari, N, Tarvainen, I, Brännström, T & Andersen, PM 2016, 'Sequence variations in C9orf72 downstream of the hexanucleotide repeat region and its effect on repeat-primed PCR interpretation: a large multinational screening study', Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, pp. 1-9. https://doi.org/10.1080/21678421.2016.1262423
Nordin, Angelica ; Akimoto, Chizuru ; Wuolikainen, Anna ; Alstermark, Helena ; Forsberg, Karin ; Baumann, Peter ; Pinto, Susana ; de Carvalho, Mamede ; Hübers, Annemarie ; Nordin, Frida ; Ludolph, Albert C. ; Weishaupt, Jochen H. ; Meyer, Thomas ; Grehl, Torsten ; Schweikert, Kathi ; Weber, Markus ; Burkhardt, Christian ; Neuwirth, Christoph ; Holmøy, Trygve ; Morita, Mitsuya ; Tysnes, Ole Bjørn ; Benatar, Michael G ; Wuu, Joanne ; Lange, Dale J. ; Bisgård, Carsten ; Asgari, Nasrin ; Tarvainen, Ilkka ; Brännström, Thomas ; Andersen, Peter M. / Sequence variations in C9orf72 downstream of the hexanucleotide repeat region and its effect on repeat-primed PCR interpretation : a large multinational screening study. In: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. 2016 ; pp. 1-9.
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T1 - Sequence variations in C9orf72 downstream of the hexanucleotide repeat region and its effect on repeat-primed PCR interpretation

T2 - a large multinational screening study

AU - Nordin, Angelica

AU - Akimoto, Chizuru

AU - Wuolikainen, Anna

AU - Alstermark, Helena

AU - Forsberg, Karin

AU - Baumann, Peter

AU - Pinto, Susana

AU - de Carvalho, Mamede

AU - Hübers, Annemarie

AU - Nordin, Frida

AU - Ludolph, Albert C.

AU - Weishaupt, Jochen H.

AU - Meyer, Thomas

AU - Grehl, Torsten

AU - Schweikert, Kathi

AU - Weber, Markus

AU - Burkhardt, Christian

AU - Neuwirth, Christoph

AU - Holmøy, Trygve

AU - Morita, Mitsuya

AU - Tysnes, Ole Bjørn

AU - Benatar, Michael G

AU - Wuu, Joanne

AU - Lange, Dale J.

AU - Bisgård, Carsten

AU - Asgari, Nasrin

AU - Tarvainen, Ilkka

AU - Brännström, Thomas

AU - Andersen, Peter M.

PY - 2016/12/6

Y1 - 2016/12/6

N2 - 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.

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