Scholarlink

Background <p>Structural variants (SVs) are important contributors to genetic disorders, yet their effects on gene dosage, particularly in a tissue-specific context, remain underexplored.</p> Methods <p>Leveraging large-scale transcriptomic data, we analyzed the tissue specific dosage disrupting effect of SVs in the human genome. To characterize this tissue-specific dosage effect, we developed a computational framework, PathoSV, which captures this impact via a Transcript Disruption Ratio (TDR). We further evaluated these tissue-specific dosage effects in patients with inherited neurodegenerative diseases.</p> Results <p>We find that dosage disruption is a key feature of rare structural variants and such effects are largely tissue specific. Further identifying such tissue-specific dosage disrupting SVs among 530 previously unresolved individuals with inherited retinal disease (IRD) or hereditary ataxia (HA), we made a molecular diagnosis in 10.1% and 3.2% of cases, respectively.&#xa0;We identified pathogenic dosage-disrupting SVs in critical, tissue-specific genes such as&#xa0;<i>EYS</i>&#xa0;in the retina and&#xa0;<i>ITPR1</i>&#xa0;and&#xa0;<i>SPAST</i>&#xa0;in the cerebellum.</p> Conclusions <p>We show that tissue-specific disruption of gene dosage is a characteristic functional consequence of rare SVs in the human genome and an important contributor to pathogenicity. Quantifying transcript-level dosage disruption clarifies the transcriptomic context in which pathogenic effects arise in complex neurodegenerative disorders and suggests a broader role for tissue-specific dosage disruption in disease. PathoSV is available at: <a href="https://github.com/xlilab/PathoSV">https://github.com/xlilab/PathoSV</a>.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Tissue-specific gene dosage disruption is a key feature and pathogenic mechanism of structural variants in the human genome

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月18日

查看全文
  • Xubing Liu,
  • Zhao Chen,
  • Qian Jiang,
  • Haoyu Shen,
  • Hongyu Liu,
  • Zhenguo Wang,
  • Zhe Li,
  • Jihong Wu,
  • Hong Jiang,
  • Xin Li

摘要

Background

Structural variants (SVs) are important contributors to genetic disorders, yet their effects on gene dosage, particularly in a tissue-specific context, remain underexplored.

Methods

Leveraging large-scale transcriptomic data, we analyzed the tissue specific dosage disrupting effect of SVs in the human genome. To characterize this tissue-specific dosage effect, we developed a computational framework, PathoSV, which captures this impact via a Transcript Disruption Ratio (TDR). We further evaluated these tissue-specific dosage effects in patients with inherited neurodegenerative diseases.

Results

We find that dosage disruption is a key feature of rare structural variants and such effects are largely tissue specific. Further identifying such tissue-specific dosage disrupting SVs among 530 previously unresolved individuals with inherited retinal disease (IRD) or hereditary ataxia (HA), we made a molecular diagnosis in 10.1% and 3.2% of cases, respectively. We identified pathogenic dosage-disrupting SVs in critical, tissue-specific genes such as EYS in the retina and ITPR1 and SPAST in the cerebellum.

Conclusions

We show that tissue-specific disruption of gene dosage is a characteristic functional consequence of rare SVs in the human genome and an important contributor to pathogenicity. Quantifying transcript-level dosage disruption clarifies the transcriptomic context in which pathogenic effects arise in complex neurodegenerative disorders and suggests a broader role for tissue-specific dosage disruption in disease. PathoSV is available at: https://github.com/xlilab/PathoSV.