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

Publication

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

Journal Paper/Review - Dec 12, 2016

Nordin Angelica, Burkhardt Christian, Neuwirth Christoph, Holmøy Trygve, Morita Mitsuya, Tysnes Ole-Bjørn, Benatar Michael, Wuu Joanne, Lange Dale J, Bisgård Carsten, Asgari Nasrin, Tarvainen Ilkka, Brännström Thomas, Weber Markus, Schweikert Kathi, Grehl Torsten, 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, Andersen Peter M

Citation

Nordin A, Burkhardt C, Neuwirth C, Holmøy T, Morita M, Tysnes O, Benatar M, Wuu J, Lange D, Bisgård C, Asgari N, Tarvainen I, Brännström T, Weber M, Schweikert K, Grehl T, Akimoto C, Wuolikainen A, Alstermark H, Forsberg K, Baumann P, Pinto S, de Carvalho M, Hübers A, Nordin F, Ludolph A, Weishaupt J, Meyer T, Andersen P. Sequence variations in C9orf72 downstream of the hexanucleotide repeat region and its effect on repeat-primed PCR interpretation: a large multinational screening study. Amyotroph Lateral Scler Frontotemporal Degener 2016; 18:256-264.

Type

Journal Paper/Review (English)

Journal

Amyotroph Lateral Scler Frontotemporal Degener 2016; 18

Publication Date

Dec 12, 2016

Issn Electronic

2167-9223

Pages

256-264

Brief description/objective

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.