• Satoko Miyatake, Hiroshi Doi, Hiroaki Yaguchi, Eriko Koshimizu, Naoki Kihara, Tomoyasu Matsubara, Yasuko Mori, Kenjiro Kunieda, Yusaku Shimizu, Tomoko Toyota, Shinichi Shirai, Masaaki Matsushima, Masaki Okubo, Taishi Wada, Misako Kunii, Ken Johkura, Ryosuke Miyamoto, Yusuke Osaki, Takabumi Miyama, Mai Satoh, Atsushi Fujita, Yuri Uchiyama, Naomi Tsuchida, Kazuharu Misawa, Kohei Hamanaka, Haruka Hamanoue, Takeshi Mizuguchi, Hiroyuki Morino, Yuishin Izumi, Takayoshi Shimohata, Kunihiro Yoshida, Hiroaki Adachi, Fumiaki Tanaka, Ichiro Yabe, and Naomichi Matsumoto.
• Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
• J. Neurol. Neurosurg. Psychiatr. 2024 May 30.

BackgroundAlthough pure GAA expansion is considered pathogenic in SCA27B, non-GAA repeat motif is mostly mixed into longer repeat sequences. This study aimed to unravel the complete sequencing of FGF14 repeat expansion to elucidate its repeat motifs and pathogenicity.MethodsWe screened FGF14 repeat expansion in a Japanese cohort of 460 molecularly undiagnosed adult-onset cerebellar ataxia patients and 1022 controls, together with 92 non-Japanese controls, and performed nanopore sequencing of FGF14 repeat expansion.ResultsIn the Japanese population, the GCA motif was predominantly observed as the non-GAA motif, whereas the GGA motif was frequently detected in non-Japanese controls. The 5'-common flanking variant was observed in all Japanese GAA repeat alleles within normal length, demonstrating its meiotic stability against repeat expansion. In both patients and controls, pure GAA repeat was up to 400 units in length, whereas non-pathogenic GAA-GCA repeat was larger, up to 900 units, but they evolved from different haplotypes, as rs534066520, located just upstream of the repeat sequence, completely discriminated them. Both (GAA)≥250 and (GAA)≥200 were enriched in patients, whereas (GAA-GCA)≥200 was similarly observed in patients and controls, suggesting the pathogenic threshold of (GAA)≥200 for cerebellar ataxia. We identified 14 patients with SCA27B (3.0%), but their single-nucleotide polymorphism genotype indicated different founder alleles between Japanese and Caucasians. The low prevalence of SCA27B in Japanese may be due to the lower allele frequency of (GAA)≥250 in the Japanese population than in Caucasians (0.15% vs 0.32%-1.26%).ConclusionsFGF14 repeat expansion has unique features of pathogenicity and allelic origin, as revealed by a single ethnic study.© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.

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