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

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 .