Clinical and genetic characterization of 535 Russian patients referred for VHLS diagnostics identified 177 causative VHL variants with significant phenotype-genotype associations, ethnic-specific variants, and demonstrated that multiple pathological changes were significantly more frequent in patients with causative variants than in those without mutations.
Key Findings
Results
A total of 177 causative VHL variants were identified in 535 Russian patients referred for VHLS diagnostics.
Variants were identified using Sanger sequencing, multiplex ligase-dependent probe amplification (MLPA), and in some cases high-throughput sequencing.
The 177 causative variants comprised 129 point mutations and 48 extended deletions.
Missense variants were the most frequent class, accounting for 60.3% of all causative variants.
Missense variants were predominantly localized at codons 167, 88, and 78.
Results
Approximately 88% of analyzed missense variants and in-frame indels led to changes directly at the HIF-α- and ELOC-binding sites of pVHL.
This finding highlights the functional clustering of pathogenic variants at key protein-protein interaction domains of the VHL protein.
HIF-α and ELOC represent the two major binding partners of pVHL relevant to its tumor suppressor function.
This structural concentration of mutations supports the pathogenic mechanism underlying VHLS.
Results
The most common clinical manifestations in patients with causative VHL variants were CNS hemangioblastoma, retinal hemangioblastomas, and clear-cell renal carcinoma.
CNS hemangioblastoma was present in 69.7% of patients with causative VHL variants.
Retinal hemangioblastomas were found in 41.4% of patients with causative variants.
Clear-cell renal carcinoma (CCRC) occurred in 27.3% of patients with causative variants.
Renal cysts were identified in 22.2%, pancreatic cysts in 20.2%, and pheochromocytoma in 7.1% of patients with causative variants.
Results
The frequency of multiple pathological changes in targeted organs was significantly higher in patients with causative VHL variants than in those without identified mutations.
Multiple pathological changes were present in 78.8% of patients with causative variants versus 21.1% of patients without identified mutations.
This difference was statistically significant (p < 0.0001).
A single case of CCRC, even in adults under 60 years of age, had a low positive predictive value of 14.7% for detection of pathogenic/likely pathogenic variants.
This suggests that isolated CCRC alone is a poor indicator for germline VHL mutation in this population.
Results
Specific VHL variants showed significant associations with patient ethnicity.
The variant c.208G>A; p.Glu70Lys was identified in four patients of East Asian ancestry only, suggesting a possible founder effect in this population.
The nonsense variant c.481C>T; p.Arg161* was found significantly more frequently in patients of Turkic ethnicities than in Slavic patients: 30.0% versus 2.5% (p = 0.0047).
No significant differences were identified in the overall profile of causative germline variants or frequencies of various VHLS clinical manifestations compared with other Slavic populations.
Results
Family screening of 87 relatives of probands identified 41 carriers of causative VHL variants.
87 relatives of probands were examined as part of the study.
41 of these relatives were found to carry causative VHL variants, representing a carrier detection rate of approximately 47% among tested relatives.
The authors note these results may contribute to improving the diagnosis of VHLS.
What This Means
This research studied a hereditary cancer condition called Von Hippel-Lindau Syndrome (VHLS) in 535 Russian patients. VHLS is caused by inherited mutations in a gene called VHL and can lead to tumors and cysts in multiple organs, including the brain, eyes, kidneys, and pancreas. The researchers used several genetic testing methods to look for mutations in these patients and found 177 different disease-causing variants, with the most common type being missense mutations — small changes in the DNA code that alter a single building block of the VHL protein. Importantly, about 88% of these mutations clustered at the parts of the VHL protein that interact with other key molecules involved in tumor suppression, helping explain why these mutations cause disease.
The study found that patients with confirmed VHL mutations most commonly developed tumors in the central nervous system (69.7%) and eyes (41.4%), followed by kidney cancer (27.3%) and various cysts. Having multiple affected organs was a strong indicator of carrying a VHL mutation — nearly 79% of mutation carriers had multiple organ involvement compared to only 21% of those without a mutation. Interestingly, having only a single kidney cancer — even at a younger age — was a poor predictor of carrying a VHL mutation, with less than 15% of such cases testing positive.
The research also revealed that certain mutations were more common in specific ethnic groups: one variant appeared only in patients of East Asian ancestry, and another was found much more often in patients of Turkic backgrounds compared to Slavic patients. Family screening identified that about half of tested relatives carried disease-causing mutations, underscoring the value of genetic testing for family members of affected individuals. These findings can help clinicians decide when and how to test patients for VHLS and may help tailor screening strategies based on a patient's ancestry and clinical presentation.
Mikhaylenko D, Vasserman N, Kuryakova N, Kuznetsova E, Gorban N, Stepanova A, et al.. (2026). Clinical and Genetic Characterization of Russian Patients with von Hippel-Lindau Syndrome.. International journal of molecular sciences. https://doi.org/10.3390/ijms27198804