C9orf72 repeat expansions in Wakayama: One potential cause of amyotrophic lateral sclerosis in the Kii Peninsula, Japan

Emori Seiji

Kume Kodai

Nakayama Yoshiaki

Ito Hidefumi

Kawakami Hideshi

Journal of the Neurological Sciences

A cluster of cases of amyotrophic lateral sclerosis (ALS) exists in the southern part of the Kii Peninsula in Japan. Although both genetic and environmental factors are thought to be causative, the critical cause of this cluster has not been identified. C9orf72 is the most common genetic factor in both familial and sporadic C9orf72-related ALS in people of European ancestry, but it is rare among Japanese populations. However, a previous report revealed that the frequency of C9orf72-related ALS was significantly higher in the cluster area. We evaluated the proportion of C9orf72 hexanucleotide repeat expansions in 99 cases of ALS diagnosed in Wakayama Prefecture, including the cluster area, by using repeat-primed polymerase chain reaction and fluorescence fragment length analysis. We found that 2 of the 99 patients (0 % of those with familial ALS and 2.4 % of those with sporadic ALS) had hexanucleotide repeat expansions in C9orf72, and long-read sequencing revealed that these expansions were causative. No expansions were observed among 90 patients with Parkinson's disease or among 90 healthy controls. Haplotype analysis with long-read sequencing data revealed that the two patients with repeat expansions shared the common haplotype with that previously reported in Finnish patients with C9orf72-related ALS, which suggests a founder effect. C9orf72 was thought to be a rare causative gene in Japan, but this study revealed that it may be relatively common in Wakayama Prefecture.

Amyotrophic lateral sclerosis

C9orf72

Hexanucleotide repeat expansion

Kii peninsula

eng

Elsevier

© 2024. This manuscript version is made available under the CC-BY-NC-ND 4.0 license https://creativecommons.org/licenses/by-nc-nd/4.0/

This is not the published version. Please cite only the published version.

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[DOI] https://doi.org/10.1016/j.jns.2024.123209 isVersionOf

日本学術振興会

Japan Society for the Promotion of Science

[Crossref Funder] https://doi.org/10.13039/501100001691

紀伊ALSのバイオマーカーと原因遺伝子同定を目的とした多施設共同レジストリー研究

Multicenter registration study aimed at identifying biomarkers and causative genes of Kii ALS

18H02743

日本学術振興会

Japan Society for the Promotion of Science

[Crossref Funder] https://doi.org/10.13039/501100001691

筋萎縮性側索硬化症の新規原因遺伝子の同定と解析

Identification and analysis of novel genes of amyotrophic lateral screlosis

21H04818

日本学術振興会

Japan Society for the Promotion of Science

[Crossref Funder] https://doi.org/10.13039/501100001691

新規リピート伸長による筋萎縮性側索硬化症の分子病態の解明

新規リピート伸長による筋萎縮性側索硬化症の分子病態の解明

23K14758