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长读测序和光学基因组映射识别了两个患有神经疾病和已知的染色体异常的患者的非编码序列中的致病性基因干扰

Kristen L Sund¹, Jie Liu^1,2, Joyce Lee³

¹Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

American journal of medical genetics. Part A

|July 23, 2024

概括

长读测序 (LRS) 和光学基因组映射 (OGM) 通过精确检测复杂的结构变异来改善神经系统综合征的遗传诊断. 这些先进的方法可以识别以前难以捉摸的致病变体,提高神经遗传疾病的诊断产量.

科学领域:

基因组学就是基因组学.
神经遗传学神经遗传学
分子诊断学分子诊断

背景情况:

下一代测序 (NGS) 在诊断复杂的神经综合征方面存在局限性,原因是检测结构变异 (SV) 的挑战.
许多患有罕见神经遗传性疾病的患者,尽管在遗传检测方面取得了进展,但仍未被诊断出来.
准确识别致病变体,特别是在非编码区域,对于诊断至关重要.

研究的目的:

评估长读序列 (LRS) 和光学基因组映射 (OGM) 在诊断患有无法解释的神经综合征和复杂染色体重排的患者的实用性.
改进结构变异的检测和解释,特别是在重复的DNA区域.
识别与神经遗传障碍相关的基因中的新型致病变体.

主要方法:

在两名已知染色体重排的患者身上进行了LRS和OGM,Sanger或NGS的结果不确.
在序列层面分析了复杂的转位,插入和反转.
集成的多原子数据,以验证已识别的非编码变体的功能影响.

主要成果:

LRS和OGM成功地解决了复杂的结构变异,包括插入/逆转的转位和复杂的染色体内逆转.
在两个患者中,在神经学相关基因 (MBD5,NKX2-1) 附近的非编码序列中确定了新的致病性断点.
鉴定变异的分子后果与患者表型 (,发育迟缓,运动障碍) 的已知疾病机制一致.

结论:

LRS和OGM为检测和解释复杂的结构变异提供了增强的能力,改善了神经遗传学中的诊断产量.
这些先进的测序技术可以在非编码区域中识别致病变体,扩大遗传诊断的范围.
对LRS/OGM分析的标准化和与多原子数据的整合将进一步推进罕见神经遗传疾病的诊断.

关键词:

染色体分析染色体分析长时间阅读阅读神经系统疾病神经系统疾病没有编码的非编码.通过光学基因组映射进行基因组映射.结构变化的结构变化.

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