Saturation genome editing maps the functional spectrum of pathogenic VHL alleles
Open accessPublished version of a preprint
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.
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- Authors
- Buckley, M., Terwagne, C., Ganner, A., Cubitt, L., Brewer, R., Kim, D.-K., Kajba, C. M., Forrester, N., Dace, P., De Jonghe, J., Shepherd, S. T. C., Sawyer, C., McEwen, M., Diederichs, S., Neumann-Haefelin, E., Turajlic, S., Ivakine, E. A., & Findlay, G. M.
- Affiliations
- The Francis Crick Institute (GB)
- University of Freiburg (DE)
- Hospital for Sick Children (CA)
- Institute of Cancer Research (GB)
- University of Toronto (CA)
- Corresponding author
- Findlay, Gregory M.
- ORCID
- Venue
- Nature Genetics
- Published
- 2024-07
- Volume
- 56
- Issue
- 7
- Pages
- 1446-1455
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC11250436
- OpenAlex
- W4400362568
- Cited by
- 62
- References
- 8
- Citations by year
- 2026: 29 · 2025: 28 · 2024: 3 · 2023: 2
- FWCI
- 15.87
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Nature Genetics (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Figshare (submittedVersion, cc-by)
- The Francis Crick Institute (cc-by)
- Funders
- Cancer Research UK (CG-MAVE)
- Francis Crick Institute (CC2190)
- Deutsche Forschungsgemeinschaft (431984000-SFB 1453)
- VHL Foundation UK/Ireland
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Renal cell carcinoma treatment
- Keywords
- von Hippel-Lindau gene, saturation genome editing, single nucleotide variants, clear cell renal cell carcinoma, pheochromocytoma, E3 ubiquitin ligase, hypoxia response, isogenic cell lines, variant interpretation, genotype-phenotype correlation, pleiotropy
- MeSH terms
- Gene Editing, Alleles, Carcinoma, Renal Cell, Humans, Kidney Neoplasms, Mutation, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Cell Line, Tumor, Von Hippel-Lindau Tumor Suppressor Protein
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