Saturation genome editing maps the functional spectrum of pathogenic VHL alleles
Abstract: To maximize the impact of precision medicine approaches, it is critical to identify genetic variants underlying disease and to accurately quantify their functional effects. A gene exemplifying the challenge of variant interpretation is the von Hippel–Lindautumor suppressor (VHL). VHL encodes an E3 ubiquitin ligase that regulates the cellular response to hypoxia. Germline pathogenic variants in VHL predispose patients to tumors including clear cell renal cell carcinoma (ccRCC) and pheochromocytoma, and somatic VHL mutations are frequently observed in sporadic renal cancer. Here we optimize and apply saturation genome editing to assay nearly all possible single-nucleotide variants (SNVs) across VHL’s coding sequence. To delineate mechanisms, we quantify mRNA dosage effects and compare functional effects in isogenic cell lines. Function scores for 2,268 VHL SNVs identify a core set of pathogenic alleles driving ccRCC with perfect accuracy, inform differential risk across tumor types and reveal new mechanisms by which variants impact function. These results have immediate utility for classifying VHL variants encountered clinically and illustrate how precise functional measurements can resolve pleiotropic and dosage-dependent genotype–phenotype relationships across complete genes
- Location
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Deutsche Nationalbibliothek Frankfurt am Main
- Extent
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Online-Ressource
- Language
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Englisch
- Notes
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Nature Genetics. - 56, 7 (2024) , 1446-1455, ISSN: 1546-1718
- Event
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Veröffentlichung
- (where)
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Freiburg
- (who)
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Universität
- (when)
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2024
- Creator
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Buckley, Megan
Terwagne, Chloé
Ganner, Athina
Cubitt, Laura
Brewer, Reid
Kim, Dong-Kyu
Kajba, Christina M.
Forrester, Nicole
Dace, Phoebe
De Jonghe, Joachim
Shepherd, Scott T. C.
Sawyer, Chelsea
McEwen, Mairead
Diederichs, Sven
Neumann-Haefelin, Elke
Turajlic, Samra
Ivakine, Evgueni A.
Findlay, Gregory M.
- DOI
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10.1038/s41588-024-01800-z
- URN
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urn:nbn:de:bsz:25-freidok-2552252
- Rights
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Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
- Last update
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14.08.2025, 11:04 AM CEST
Data provider
Deutsche Nationalbibliothek. If you have any questions about the object, please contact the data provider.
Associated
- Buckley, Megan
- Terwagne, Chloé
- Ganner, Athina
- Cubitt, Laura
- Brewer, Reid
- Kim, Dong-Kyu
- Kajba, Christina M.
- Forrester, Nicole
- Dace, Phoebe
- De Jonghe, Joachim
- Shepherd, Scott T. C.
- Sawyer, Chelsea
- McEwen, Mairead
- Diederichs, Sven
- Neumann-Haefelin, Elke
- Turajlic, Samra
- Ivakine, Evgueni A.
- Findlay, Gregory M.
- Universität
Time of origin
- 2024
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Saturation genome editing maps the functional spectrum of pathogenic VHL alleles
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Reducing uncertainty in genetic testing with Saturation Genome Editing
Gene editing the phytoene desaturase alleles of Cavendish banana using CRISPR/Cas9
Identification of 3 novel VHL germ-line mutations in Danish VHL patients
Von Hippel–Lindau (VHL) disease and VHL-associated tumors in Indian subjects: VHL gene testing in a resource constraint setting
Saturation genome editing of BAP1 functionally classifies somatic and germline variants
Metastatic Pheochromocytoma Diagnosed with 131I-MIBG SPECT/CT Imaging in a Patient with Pathogenic VHL Mutation
CpG methylation profiling in VHL related and VHL unrelated renal cell carcinoma
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Identification of pathogenic variants in cancer genes using base editing screens with editing efficiency correction
Saturation genome editing of DDX3X clarifies pathogenicity of germline and somatic variation
Saturation genome editing maps the functional spectrum of pathogenic VHL alleles
Removal of alleles by genome editing (RAGE) against deleterious load
Reducing uncertainty in genetic testing with Saturation Genome Editing
Gene editing the phytoene desaturase alleles of Cavendish banana using CRISPR/Cas9
Identification of 3 novel VHL germ-line mutations in Danish VHL patients
Von Hippel–Lindau (VHL) disease and VHL-associated tumors in Indian subjects: VHL gene testing in a resource constraint setting
Saturation genome editing of BAP1 functionally classifies somatic and germline variants
Metastatic Pheochromocytoma Diagnosed with 131I-MIBG SPECT/CT Imaging in a Patient with Pathogenic VHL Mutation
CpG methylation profiling in VHL related and VHL unrelated renal cell carcinoma
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Identification of pathogenic variants in cancer genes using base editing screens with editing efficiency correction