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.
- Clinical Decision-Making
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.
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