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

IF 8.7 1区医学 Q1 CLINICAL NEUROLOGY Journal of Neurology, Neurosurgery, and Psychiatry Pub Date : 2024-11-18 DOI:10.1136/jnnp-2024-333541

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, Naomichi Matsumoto

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Abstract

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.

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日文 SCA27B（GAA-FGF14 共济失调）的完整纳米孔重复测序。

背景：虽然纯GAA扩增被认为是SCA27B的致病因素，但非GAA重复序列大多混杂在较长的重复序列中。本研究旨在对 FGF14 重复扩增进行完整测序，以阐明其重复基序和致病性：方法：我们在460名未进行分子诊断的成人型小脑共济失调患者和1022名对照者以及92名非日本对照者组成的日本队列中筛查了FGF14重复扩增，并对FGF14重复扩增进行了纳米孔测序：结果：在日本人群中，主要观察到GCA基序为非GAA基序，而在非日本对照组中则经常检测到GGA基序。在所有长度正常的日本 GAA 重复等位基因中都能观察到 5'-common 侧翼变体，这表明其在减数分裂过程中具有稳定性，可防止重复扩增。在患者和对照组中，纯合子 GAA 重复序列的长度最多为 400 个单位，而非致病性 GAA-GCA 重复序列的长度更大，可达 900 个单位，但它们是从不同的单倍型演化而来的，因为位于重复序列上游的 rs534066520 完全可以将它们区分开来。(GAA)≥250和(GAA)≥200都在患者中富集，而(GAA-GCA)≥200在患者和对照组中的观察结果相似，这表明(GAA)≥200对小脑共济失调的致病阈值。我们发现了 14 名 SCA27B 患者（3.0%），但他们的单核苷酸多态性基因型显示日本人和白种人的始祖等位基因不同。SCA27B在日本人中的低发病率可能是由于日本人中(GAA)≥250的等位基因频率低于白种人（0.15% vs 0.32%-1.26%）：结论：一项单一种族研究显示，FGF14重复扩增具有独特的致病性和等位基因来源。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Neurology, Neurosurgery, and Psychiatry 医学-精神病学

CiteScore

15.70

自引率

1.80%

发文量

888

审稿时长

6 months

期刊介绍： The Journal of Neurology, Neurosurgery & Psychiatry (JNNP) aspires to publish groundbreaking and cutting-edge research worldwide. Covering the entire spectrum of neurological sciences, the journal focuses on common disorders like stroke, multiple sclerosis, Parkinson’s disease, epilepsy, peripheral neuropathy, subarachnoid haemorrhage, and neuropsychiatry, while also addressing complex challenges such as ALS. With early online publication, regular podcasts, and an extensive archive collection boasting the longest half-life in clinical neuroscience journals, JNNP aims to be a trailblazer in the field.