在单一性疾病中识别同名致病变体,通过将外体与转录组测序集成
Lin Zhang1, Haijuan Lou2, Yanhong Huang3
1Prenatal Diagnosis Center, Peking University People's Hospital, Beijing, China.
The Journal of molecular diagnostics : JMD
|January 27, 2024
概括
外基因组测序与内基和同义变体作斗争. 这项研究整合了转录组测序,以识别这些具有挑战性的变体,改善遗传疾病诊断.
科学领域:
- 基因组学和转录基因组学
- 临床诊断 临床诊断 临床诊断
- 人类遗传学 人类遗传学
背景情况:
- 外体序列测序是孟德尔病的首要临床工具,但在诊断内部变异或同名编码子内的变异方面仍然存在挑战.
- 由于目前针对特定变异类型的基因诊断方法的局限性,大量患者仍未被诊断出来.
研究的目的:
- 开发和验证一个工作流程,集成外体测序,全血转录组测序和in silico工具.
- 在患有未解决遗传疾病的患者中识别和功能验证剪接改变的内基和同义变异.
主要方法:
- 构建一个全血转录组数据库2981在线孟德尔在人 (OMIM) 疾病遗传基因.
- 整合外基因组测序,血液转录基因组测序,以及用于变体识别的in silico预测.
- 用于功能验证已识别的剪接改变变异的RNA测序.
主要成果:
- 在八名患者中,使用综合多种OMIC管道识别了七种同名变体.
- 对于四种变异建立了用于拼接改变的新功能证据:c.981G>A (PIGN),c.1161A>G (ALPL),c.858G>A (ATP6AP2) 和c.1011G>T (MTHFR).
- RNA测序证实了这些变体引起的异常拼接,扩大了这些基因已知的变体谱.
结论:
- 结合多omics数据,特别是RNA测序,是可行的和强大的识别拼接改变变体.
- 同义变异是一种至关重要的,经常被忽视的,导致尚未解决的遗传疾病的因素.
- 拟议的工作流通过解决标准外基因组测序的局限性来提高孟德尔疾病的诊断产量.
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