通过针对性的并行长度读取测序分析的德国患者队列中的重复相关性
Hannes Erdmann1,2, Annalisa Schaub1,2, Morghan C Lucas1,2,3
1Medical Genetics Center (MGZ) Munich, 80335 Munich, Germany.
Brain : a journal of neurology
|September 3, 2025
概括
长读数测序 (LRS) 为遗传性成人发病症提供了精确的诊断解决方案,在三分之一以上的患者中确定了重复扩散,并使得更好的遗传诊断成为可能. 这种先进的方法应该取代临床遗传学的传统PCR方法.
科学领域:
- 遗传学和基因组学
- 神经学
- 分子诊断
背景情况:
- 遗传性成人发病性形是一种多样化的疾病群体,通常是由重复扩张引起的.
- 目前的诊断方法如PCR是劳动密集且缺乏精度.
- 长读数测序 (LRS) 为准确的基因分析提供了一个有希望的替代方案.
研究的目的:
- 评估临床纳米孔Cas9向测序 (Clin-CATS) 的诊断实用性,用于分析成人发病性缩症患者的重复扩张.
- 确定已知反复关联性的频率和衰退性疾病的载体频率.
- 描述表型并确定新的重复配置.
主要方法:
- 使用临床纳米孔Cas9向测序 (Clin-CATS) 在513名成人发病性症患者中.
- 进行并行深度重复分析以确定致病性扩散.
- 测序了另外347名患者的特定重复扩张 (ZFHX3).
主要成果:
- 在33. 3%的患者中证实了与重复相关的,包括罕见类型和流行的RFC1谱系障碍和SCA27B.
- 在4. 7%的患者中发现了潜在的致病性FGF14扩张;没有发现SCA4.
- 在6. 4%的患者中观察到双重诊断,其中RFC1频谱障碍的携带频率高 (7. 2%) 和弗里德里希的低频率重新评估 (0. 8%).
结论:
- 长读数测序 (LRS) 在遗传性瘤中为综合重复分析提供了显著的诊断优势.
- 应采用LRS作为临床遗传学的标准,取代旧的方法,如南方斑块和PCR.
- 为了提高诊断精度,建议重新评估基因型与表型的相关性,并包括超出重复长度的参数.
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