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Original research
Genotype–phenotype correlations and clinical outcomes of patients with von Hippel-Lindau disease with large deletions
  1. Kenan Zhang1,2,3,
  2. Wuping Yang1,2,3,
  3. Kaifang Ma1,2,
  4. Jianhui Qiu1,2,
  5. Lei Li1,2,
  6. Yawei Xu1,2,
  7. Zedan Zhang1,2,
  8. Chaojian Yu1,2,
  9. Jingcheng Zhou1,2,
  10. Yanqing Gong1,2,
  11. Lin Cai1,2,3,
  12. Kan Gong1,2,3
  1. 1 Department of Urology, Peking University First Hospital, Beijing, China
  2. 2 Institute of Urology, Peking University, Beijing, China
  3. 3 Hereditary Kidney Cancer Research Center, Peking University First Hospital, Beijing, China
  1. Correspondence to Professor Kan Gong, Department of Urology, Peking University First Hospital, Beijing, China; gongkan_pku{at}; Dr Lin Cai; drcailin{at}


Background Approximately 20%–40% of patients with von Hippel-Lindau (VHL) disease, an autosomal dominant hereditary disease, exhibit large deletions (LDs). Few studies have focused on this population. Hence, we aimed to elucidate the genotype–phenotype correlations and clinical outcomes in VHL patients with LDs.

Methods In this retrospective study, we included 119 patients with VHL disease from 50 unrelated families in whom LDs were detected using traditional and next-generation sequencing methods. Other germline mutations were confirmed by Sanger sequencing. Genotype–phenotype correlations and survival were analysed in different groups using Kaplan-Meier and Cox regression. We also evaluated therapeutic response to tyrosine kinase inhibitor (TKI) therapy.

Results The overall penetrance of patients aged <60 was 95.2%. Two VHL patients with LDs also carried CHEK2 and FLCN germline mutations. An earlier age of onset of retinal haemangioblastoma was observed in the next generation. Patients with exon 2 deletion of VHL had an earlier onset age of renal cell carcinoma and pancreatic lesions. The risk of renal cell carcinoma was lower in VHL patients with LDs and a BRK1 deletion. The group with earlier age of onset received poorer prognosis. Four of eight (50%) patients showed partial response to TKI therapy.

Conclusion The number of generations and the status of exon 2 could affect age of onset of VHL-related manifestations. Onset age was an independent risk factor for overall survival. TKI therapy was effective in VHL patients with LDs. Our findings would further support clinical surveillance and decision-making processes.

  • Heredity
  • Urology
  • Genotype
  • Clinical Decision-Making
  • Genetics

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

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Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

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  • KZ and WY contributed equally.

  • LC and KG contributed equally.

  • Contributors KG and LC conceived the study and participated in its design, data acquisition and quality control. KZ and YW dealt with the clinical data and drafted the manuscript. KM, QJ, LL, ZZ and XY performed the gene tests and collected detailed clinical data of patients. JZ, CY and GY dealt with the final typesetting and revised the manuscript. KG is responsible for the overall content of the manuscript acting as guarantor. All authors contributed to manuscript revision and approved the submitted version.

  • Funding This work was supported by the National High Level Hospital Clinical Research Funding (High Quality Clinical Research Project of Peking University First Hospital, 2022CR75), the National Natural Science Foundation of China (no: 82141103, 82172617, 82172665, 81872081), the Scientific Research Seed Fund of Peking University First Hospital (2021SF01), the Capital’s Funds for Health Improvement and Research (2022-2-4074) and the Sino-Russian Mathematics Center.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.