Complete nanopore repeat sequencing of SCA27B (GAA- FGF14 ataxia) in Japanese.

Autor:	Miyatake S; Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.; Department of Clinical Genetics, Yokohama City University Hospital, Yokohama, Japan., Doi H; Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan., Yaguchi H; Department of Neurology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan., Koshimizu E; Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan., Kihara N; Department of Neurology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan., Matsubara T; Department of Neurology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan., Mori Y; Department of Neurology, Gifu University Graduate School of Medicine, Gifu, Japan., Kunieda K; Department of Neurology, Gifu University Graduate School of Medicine, Gifu, Japan., Shimizu Y; Department of Neurology, Ina Central Hospital, Ina, Japan., Toyota T; Department of Neurology, University of Occupational and Environmental Health School of Medicine, Kitakyushu, Japan., Shirai S; Department of Neurology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan., Matsushima M; Department of Neurology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan., Okubo M; Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan., Wada T; Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan., Kunii M; Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan., Johkura K; Department of Neurology, Yokohama Brain and Spine Center, Yokohama, Japan., Miyamoto R; Department of Neurology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan., Osaki Y; Department of Neurology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan., Miyama T; Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan., Satoh M; Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan., Fujita A; Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan., Uchiyama Y; Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.; Department of Rare Disease Genomics, Yokohama City University Hospital, Yokohama, Japan., Tsuchida N; Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.; Department of Rare Disease Genomics, Yokohama City University Hospital, Yokohama, Japan., Misawa K; Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.; RIKEN Center for Advanced Intelligence Project, Tokyo, Japan., Hamanaka K; Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.; Institute for the Advanced Study of Human Biology, Kyoto University, Kyoto, Japan., Hamanoue H; Department of Clinical Genetics, Yokohama City University Hospital, Yokohama, Japan., Mizuguchi T; Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan., Morino H; Department of Medical Genetics, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan., Izumi Y; Department of Neurology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan., Shimohata T; Department of Neurology, Gifu University Graduate School of Medicine, Gifu, Japan., Yoshida K; Department of Neurology, JA Nagano Koseiren, Kakeyu-Misayama Rehabilitation Center Kakeyu Hospital, Ueda, Japan.; Department of Brain Disease Research, Shinshu University School of Medicine, Matsumoto, Japan., Adachi H; Department of Neurology, University of Occupational and Environmental Health School of Medicine, Kitakyushu, Japan., Tanaka F; Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan., Yabe I; Department of Neurology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan naomat@yokohama-cu.ac.jp yabe@med.hokudai.ac.jp., Matsumoto N; Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan naomat@yokohama-cu.ac.jp yabe@med.hokudai.ac.jp.; Department of Clinical Genetics, Yokohama City University Hospital, Yokohama, Japan.; Department of Rare Disease Genomics, Yokohama City University Hospital, Yokohama, Japan.
Jazyk:	angličtina
Zdroj:	Journal of neurology, neurosurgery, and psychiatry [J Neurol Neurosurg Psychiatry] 2024 Nov 18; Vol. 95 (12), pp. 1187-1195. Date of Electronic Publication: 2024 Nov 18.
DOI:	10.1136/jnnp-2024-333541
Abstrakt:	Background: Although 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. Methods: We 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. Results: In 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%). Conclusions: FGF14 repeat expansion has unique features of pathogenicity and allelic origin, as revealed by a single ethnic study. Competing Interests: Competing interests: None declared. (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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