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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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      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.\u00a0We identified pathogenic dosage-disrupting SVs in critical, tissue-specific genes such as\u00a0\n                      <jats:italic>EYS<\/jats:italic>\n                      \u00a0in the retina and\u00a0\n                      <jats:italic>ITPR1<\/jats:italic>\n                      \u00a0and\u00a0\n                      <jats:italic>SPAST<\/jats:italic>\n                      \u00a0in the cerebellum.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      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:\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/github.com\/xlilab\/PathoSV\" ext-link-type=\"uri\">https:\/\/github.com\/xlilab\/PathoSV<\/jats:ext-link>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13073-026-01653-7","type":"journal-article","created":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T13:35:56Z","timestamp":1776519356000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Tissue-specific gene dosage disruption is a key feature and pathogenic mechanism of structural variants in the human genome"],"prefix":"10.1186","volume":"18","author":[{"given":"Xubing","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhao","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoyu","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyu","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenguo","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhe","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jihong","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,18]]},"reference":[{"issue":"7809","key":"1653_CR1","doi-asserted-by":"publisher","first-page":"444","DOI":"10.1038\/s41586-020-2287-8","volume":"581","author":"RL Collins","year":"2020","unstructured":"Collins RL, et al. 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