Abstract
Background
Von Hippel–Lindau (VHL) syndrome is a rare autosomal dominant multisystem tumour syndrome caused by germline VHL mutations. The traditional classification of VHL syndrome, which is largely based on pheochromocytoma penetrance, is insufficient for individualised surveillance and management. This study aimed to improve mutation-specific risk stratification and define genotype–phenotype correlations of recurrent hotspot mutations in a large Chinese cohort.
Methods
This retrospective single-centre study included 674 patients with VHL disease from 283 unrelated families. Four recurrent hotspot mutation subtypes were analysed: codon 65 missense mutations, exon 2 deletion, c.481C > T, and c.224_226del. Kaplan–Meier analysis and univariate and multivariate Cox regression models were used to assess age-related tumour risks and survival outcomes.
Results
Codon 65 missense mutations were associated with a lower risk of retinal angioma and pheochromocytoma, indicating a relatively mild phenotype. Exon 2 deletion was characterised by a higher prevalence, earlier onset, and increased age-related risk of retinal angioma and worse renal cell carcinoma (RCC)-specific survival. Increased prevalences and age-related risks of central nervous system hemangioblastoma (CHB), RCC, and pancreatic cysts or tumours were associated with c.481C > T mutations. The c.224_226del subtype showed a distinct CHB-predominant phenotype, with higher CHB incidence, earlier onset, lower pancreatic lesion risk, and higher overall mortality.
Conclusion
Recurrent hotspot VHL mutation subtypes were associated with distinct clinical phenotypes and prognostic patterns. Mutation subtype-based classification (covering 19.6% of patients with VHL syndrome) may provide more precise guidance for surveillance, clinical decision-making, and genetic counselling than traditional broad classification models.
Graphical abstract
Supplementary Information
The online version contains supplementary material available at https://doi.org/10.1007/s00432-026-06564-z.
Keywords: Von Hippel–Lindau disease, VHL mutation, Genotype–phenotype correlation, Hotspot mutation, Risk stratification
Introduction
Von Hippel–Lindau (VHL) disease (MIM: 193,300) is an autosomal dominant disorder caused by mutations in the VHL gene (Kaelin 2022; Rednam et al. 2025). VHL is located on the short arm of chromosome 3 (3p25-26). The incidence of VHL syndrome is approximately 1 in 36,000 to 1 in 50,000. Patients present with multicentric and multiorgan tumours, including clear cell renal cell carcinoma (RCC), central nervous system hemangioblastoma (CHB), retinal angioma (RA), pheochromocytoma, and pancreatic cysts or tumours (PCT) (Liao et al. 2024; Ganner et al. 2025). According to phenotypic characteristics, VHL syndrome can be divided into two subtypes; type 1 is characterised by a lower incidence of pheochromocytoma and higher risk of RCC, whereas type 2 is characterised by a higher likelihood of developing pheochromocytoma (Nielsen et al. 2016). However, this traditional two-subtype classification method does not sufficiently describe all patients with VHL syndrome. Furthermore, surveillance and individualised interventions are urgently required as over 90% of patients with pathogenic mutations exhibit VHL syndrome–related symptoms before the age of 65 (Peng et al. 2017).
VHL encodes an E3 ubiquitin ligase with key regulatory functions. This enzyme degrades numerous substrates, including hypoxia-inducing factor (HIF-α). However, VHL mutations impair its functions, leading to the stable presence of HIF-α and continuous activation of downstream angiogenesis, ultimately promoting the formation of malignant tumours (Buckley et al. 2024).
Several studies have found significant associations between genotypes and phenotypes in patients with VHL syndrome (Binderup et al. 2016; Bangiyeva et al. 2009; Suzuki et al. 2024). Such genotype–phenotype relationships may provide clues to further our understanding of disease mechanisms and personalised treatment. For example, Hong et al. (2019) showed that patients with missense mutations exhibited significant phenotypic heterogeneity. In addition, Liu et al. (2018) demonstrated that missense mutations located in the HIF-α binding region increased the risk of CHB while reducing the risk of pheochromocytoma. Previous studies have analysed genotype–phenotype characteristics to categorise VHL into different types based on mutation patterns or regions. However, this classification approach may be limited by the overrepresentation of specific mutations (e.g., the mutation at amino acid 167) or the particularly distinct phenotypes associated with such mutations, which could influence the generalizability of genotype–phenotype analyses (Li et al. 2025).
In this study, we aimed to identify detailed genotype–phenotype relationships of the main hotspot mutations based on mutation types, including codon 65 missense mutations (HIF-α binding site missense mutations), exon 2 deletion (truncation mutation, TR), c.481C > T (TR), and c.224_226del (TR). Ultimately, we aimed to provide new VHL syndrome subtypes based on these hotspot mutations for improved monitoring and treatment.
Methods
Ethical considerations
The present study was approved by the Ethics Committee of Peking University First Hospital (Beijing, China) (Ethics no.2026R0246). Informed consent was obtained from individuals who participated in the study or their legal guardians.
Subject and recruitment
This retrospective study included patients diagnosed with VHL syndrome between January 2010 and December 2022 at the Peking University First Hospital, the only international VHL Clinical Care Centre in China. Patients carrying a germline VHL mutation or fulfilling the clinical diagnostic criteria for VHL syndrome were eligible for inclusion (Rednam et al. 2025; Molino et al. 2006). After excluding patients with incomplete clinical data, 674 patients from 283 unrelated families were included in the study. Clinical information, including sex, age, involved lesions, age at onset, and survival time, was collected from surviving patients, family members, or medical records. Age at onset was defined as the age at first onset of VHL syndrome-related symptoms. All affected patients and asymptomatic carriers from VHL families were followed up to determine the age at onset of the five major VHL-associated lesions, including CHB, RA, RCC, PCT, and pheochromocytoma. Follow-ups were performed until death or December 2023.
This study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Peking University First Hospital. Written informed consent was obtained from all patients or their legal guardians.
Genetic testing
Peripheral blood samples were collected from each enrolled patient unless the patient declined to participate or had died. Genomic DNA was extracted from peripheral blood samples using a DNA extraction kit (Tiangen, China). The three exons of the VHL gene and their flanking intronic sequences were amplified by polymerase chain reaction and analysed using Sanger sequencing to determine germline VHL mutation status (Wang et al. 2014). Variant nomenclature was based on the VHL reference transcript NM_000551.4 and protein reference sequence NP_000542.1.The patients were divided into VHL missense mutations and truncation mutations based on the genetic analysis. Patients with nonsense mutations, small indels and inserts, splice-site mutations, and copy number variants, which would result in truncated proteins, were categorised as having truncation mutations. For truncation mutations, multiplex ligation-dependent probe amplification (MLPA) was performed using the SALSA MLPA probe mix (MRC Holland, Amsterdam, the Netherlands) according to the manufacturer’s instructions. All genetic testing results were independently reviewed by two investigators to minimise interpretation errors. The mutation spectra of the 674 patients with VHL syndrome are shown in Table 1.
Table 1.
Clinical and mutational characteristics of the overall cohort
| Missense mutations | Truncating mutations | Truncating mutations | Truncating mutations | |||||
|---|---|---|---|---|---|---|---|---|
| Codon 65 MMs | oMMs | Exon2 del | oTR(Exon2) | c.481C > T | oTR(481) | c.224-226 del | oTR(224-226) | |
| Subjects | 49 | 296 | 32 | 297 | 23 | 306 | 28 | 301 |
| Unrelated families | 16 | 132 | 11 | 133 | 15 | 129 | 10 | 134 |
| Sex, n(%) | ||||||||
| Male | 39(79.6) | 161(54.4) | 19(59.4) | 166(55.9) | 12(52.2) | 173(56.5) | 16(57.1) | 169(56.1) |
| Female | 10(20.4) | 135(45.6) | 13(40.6) | 131(44.1) | 11(47.8) | 133(43.5) | 12(42.9) | 132(43.9) |
| Age (mean ± SD) | 37.7 ± 14.7 | 38.3 ± 14.8 | 38.8 ± 15.0 | 38.2 ± 14.7 | 37.9 ± 14.8 | 38.2 ± 14.7 | 37.1 ± 14.8 | 38.2 ± 14.7 |
| Clinical type, n(%) | ||||||||
| Type 1 | 47(95.9) | 206(69.6) | 29(90.6) | 276(92.9) | 20(87.0) | 285(93.1) | 28(100) | 277(92.0) |
| Type 2 | 2(4.1) | 90(30.4) | 3(9.4) | 21(7.1) | 3(13.0) | 21(6.9) | 0 | 24(8.0) |
| Onset age, n(%) | ||||||||
| ≤ 30 years | 22(44.9) | 136(45.9) | 8(25.0) | 149(50.2) | 14(60.9) | 151(49.3) | 11(39.3) | 154(51.2) |
| > 30 years | 23(46.9) | 130(43.9) | 23(71.9) | 117(39.4) | 7(30.4) | 125(40.8) | 13(46.4) | 119(39.5) |
| Asymptomatic | 4(8.2) | 30(10.1) | 1(3.1) | 31(10.4) | 2(8.7) | 30(9.8) | 4(14.3) | 28(9.3) |
| Affected lesion, n(%) | ||||||||
| CHB | 34(69.4) | 167(56.4) | 23(71.9) | 211(71.0) | 20(87.0) | 214(69.9) | 21(75.0) | 213(70.8) |
| RA | 3(6.1) | 52(17.6) | 13(40.6) | 69(23.2) | 6(26.1) | 76(24.8) | 3(10.7) | 79(26.2) |
| RCC | 25(51.0) | 129(43.6) | 15(46.9) | 157(52.9) | 17(73.9) | 155(50.7) | 9(32.1) | 163(54.2) |
| PHEO | 2(4.1) | 90(30.4) | 3(9.4) | 21(7.1) | 3(13.0) | 21(6.9) | 0 | 24(8.0) |
| PCT | 25(51.0) | 136(45.9) | 12(37.5) | 152(51.2) | 17(73.9) | 147(48.0) | 5(17.9) | 159(52.8) |
| Death and cause, n(%) | ||||||||
| Death(any cause) | 9(18.4) | 52(17.6) | 10(31.3) | 65(21.9) | 1(4.3) | 74(24.2) | 11(39.3) | 64(21.3) |
| CHB | 6(12.2) | 33(11.1) | 6(18.8) | 42(14.1) | 1(4.3) | 47(15.4) | 10(35.7) | 38(12.6) |
| RCC | 2(4.1) | 12(4.1) | 4(12.5) | 18(6.1) | 0 | 22(7.2) | 1(3.6) | 21(7.0) |
| Others | 1(2.0) | 7(2.4) | 0 | 5(1.7) | 0 | 5(1.6) | 0 | 5(1.7) |
| Mutation type, n(%) | ||||||||
| c.193 T > C p.Ser65Pro | 9(18.4) | |||||||
| c.194C > G p.Ser65Trp | 10(20.4) | |||||||
| c.194C > T p.Ser65Leu | 30(61.2) | |||||||
Data are presented as n (%). Continuous variables are presented as mean ± standard deviation
MMs, missense mutations; oMMs, other codons missense mutations; oTR, other truncating mutations; del, deletion; SD, standard deviation; CHB, central nervous system hemangioblastoma; RA, retinal anginoma; RCC, renal cell carcinoma; PHEO, pheochromocytoma; PCT, pancreatic cyst or tumor
Statistical analysis
Wilcoxon rank-sum tests were used for continuous variables and the pearson chi-square test was used for categorical variables. Survival time was defined as the time from birth to death or the end of the follow-up period. Kaplan–Meier analysis with log-rank testing was performed to estimate the age-related risks of VHL-associated lesions and age at death. Univariate and multivariate Cox proportional hazards regression models were used to determine whether sex, birth year, family history, and clinical type were independent risk factors for VHL-related manifestations and mortality. Statistical significance was defined as a two-sided P-value < 0.05.
Results
Overall clinical and pathological characteristics
A total of 674 patients with VHL syndrome from 283 unrelated families were enrolled in this study. Among them, 345 patients carried missense mutations and 329 carried truncation mutations, indicating a relatively balanced distribution between the two major mutation categories. Further analysis of the recurrent mutation subtypes (covering 19.6% of patients with VHL syndrome) showed that 49 patients from 16 unrelated families harboured codon 65 missense mutations, 32 patients from 11 unrelated families had exon 2 deletion, 23 patients from 15 unrelated families carried c.481C > T, and 28 patients from 10 unrelated families harboured c.224_226del. Among the codon 65 missense mutations, c.194C > T (p.Ser65Leu) was the predominant subtype, accounting for 61.2% of the cases, followed by c.194C > G (p.Ser65Trp) and c.193 T > C (p.Ser65Pro), accounting for 20.4% and 18.4%, respectively. These findings demonstrated that multiple recurrent VHL mutation subtypes were present in this cohort, which provided the basis for subsequent genotype–phenotype analyses (Table 1).
Reduced risk of RA and pheochromocytoma in patients with codon 65 missense mutations
To further investigate the clinicopathological characteristics associated with specific VHL mutations, missense mutations were classified into three subgroups for the primary analysis: codon 65 mutations, other missense mutations (oMMs), and truncation mutations (TRs) (Fig. 1). For secondary analysis, other missense mutations were further divided into other HIF-α binding site missense mutations (oHMs) and non-HIF-α binding site missense mutations (nHMs) (Fig. 2).
Fig. 1.
Missense mutation classification in VHL protein. Created with Biorender.com
Fig. 2.
Comparison of age-related risks in Codon 65 MMs, oMMs and TR. a All the five VHL-associated tumor, b CHB, c RA, d RCC, e PCT, f PHEO. MMs, missense mutations; oMMs, other codons missense mutations; TR, truncating mutations; CHB, central nervous system hemangioblastoma; RA, retinal anginoma; RCC, renal cell carcinoma; PHEO, pheochromocytoma; PCT, pancreatic cyst or tumor
Compared with patients carrying other missense mutations and truncation mutations, those with codon 65 mutations have lower incidences of RA (6.1% vs. 17.6% vs. 24.9%, P < 0.001) and pheochromocytoma (4.1% vs. 30.4% vs. 37.3%, P < 0.001; Table 2). We found that codon 65 mutations were associated with a lower age-related risk of RA and pheochromocytoma (both P < 0.001) than other missense mutations and truncation mutations (Fig. 2). Cox regression analysis demonstrated that codon 65 mutations were associated with a significantly lower age-related risk of RA than truncation mutations (hazard ratio [HR], 0.198; 95% confidence interval [CI], 0.062–0.627; P = 0.006; Supplement Table 1). No significant differences in survival were identified among patients with codon 65 missense mutations, other missense mutations, or truncation mutations (Supplement Table 2; Supplement Fig. 1).
Table 2.
Clinical and mutational characteristics of Codon 65 MMs, oMMs and TR
| Missense mutations | TR | P value | ||
|---|---|---|---|---|
| Codon 65 MMs | oMMs | |||
| Subjects | 49 | 296 | 329 | |
| Unrelated families | 16 | 132 | 144 | 0.541 |
| Sex, n(%) | 0.004 | |||
| Male | 39(79.6) | 161(54.4) | 185(56.2) | |
| Female | 10(20.4) | 135(45.6) | 144(43.8) | |
| Age (mean ± SD) | 37.7 ± 14.7 | 38.3 ± 14.8 | 37.9 ± 14.9 | 0.494 |
| Clinical type, n(%) | < 0.001 | |||
| Type 1 | 47(95.9) | 206(69.6) | 305(92.7) | |
| Type 2 | 2(4.1) | 90(30.4) | 24(7.3) | |
| Onset age, n(%) | 0.827 | |||
| ≤ 30 years | 22(44.9) | 136(45.9) | 165(50.1) | |
| > 30 years | 23(46.9) | 130(43.9) | 132(40.1) | |
| Asymptomatic | 4(8.2) | 30(10.1) | 32(9.7) | |
| Affected lesion, n(%) | ||||
| CHB | 34(69.4) | 167(56.4) | 234(71.1) | < 0.001 |
| RA | 3(6.1) | 52(17.6) | 82(24.9) | 0.003 |
| RCC | 25(51.0) | 129(43.6) | 172(52.3) | 0.088 |
| PHEO | 2(4.1) | 90(30.4) | 24(7.3) | < 0.001 |
| PCT | 25(51.0) | 136(45.9) | 164(49.8) | 0.572 |
| Death and cause, n(%) | ||||
| Death(any cause) | 9(18.4) | 52(17.6) | 75(22.8) | 0.253 |
| CHB | 6(12.2) | 33(11.1) | 48(14.6) | 0.575 |
| RCC | 2(4.1) | 12(4.1) | 22(6.7) | |
| Others | 1(2.0) | 7(2.4) | 5(1.5) | |
| Mutation type, n(%) | ||||
| c.193 T > C p.Ser65Pro | 9(18.4) | |||
| c.194C > G p.Ser65Trp | 10(20.4) | |||
| c.194C > T p.Ser65Leu | 30(61.2) | |||
Data are presented as n (%). Continuous variables are presented as mean ± standard deviation
MMs, missense mutations; oMMs, other codons missense mutations; TR, truncating mutations; SD, standard deviation; CHB, central nervous system hemangioblastoma; RA, retinal anginoma; RCC, renal cell carcinoma; PHEO, pheochromocytoma; PCT, pancreatic cyst or tumor
P value < 0.05 will be bold
Results were obtained when codon 65 mutations were compared with oHMs and nHMs. Patients with codon 65 mutations had a significantly lower prevalence of pheochromocytoma than those with oHMs and nHMs (4.1% vs. 15.9% vs. 43.0%, P < 0.001; Supplement Table 3). A lower age-related risk of pheochromocytoma was found in patients with codon 65 mutations (P < 0.001; Fig. 3). No significant differences were found in age-related tumour risk or survival in the Cox regression analyses (Supplement Table 4; Supplement Table 5; Supplement Fig. 2).
Table 3.
Clinical and mutational characteristics of patients with MMs, Exon2 del and oTR(Exon2 del)
| MMs | Exon 2 del | oTR(Exon2) | P value | |
|---|---|---|---|---|
| Patients | 345 | 32 | 297 | |
| Unrelated families | 138 | 11 | 132 | |
| Sex, n(%) | 0.839 | |||
| Male | 200(58.0) | 19(59.4) | 166(55.9) | |
| Female | 145(42.0) | 13(40.6) | 131(44.1) | |
| Age (mean ± SD) | 38.3 ± 14.8 | 38.8 ± 15.0 | 38.2 ± 14.7 | |
| Clinical type, n(%) | < 0.001 | |||
| Type 1 | 253(73.3) | 29(90.6) | 276(92.9) | |
| Type 2 | 92(26.7) | 3(9.4) | 21(7.1) | |
| Onset age, n(%) | 0.531 | |||
| ≤ 30 years | 159(46.1) | 8(25.0) | 149(50.2) | |
| > 30 years | 152(44.1) | 23(71.9) | 117(39.4) | |
| Asymptomatic | 34(9.8) | 1(3.1) | 31(10.4) | |
| Affected lesion, n(%) | ||||
| CHB | 201(58.3) | 23(71.9) | 211(71.0) | 0.002 |
| RA | 55(15.9) | 13(40.6) | 69(23.2) | 0.001 |
| RCC | 154(44.6) | 15(46.9) | 157(52.9) | 0.113 |
| PHEO | 92(26.7) | 3(9.4) | 21(7.1) | < 0.001 |
| PCT | 161(46.7) | 12(37.5) | 152(51.2) | 0.241 |
| Death and cause, n(%) | ||||
| Death (any cause) | 61(17.7) | 10(31.3) | 65(21.9) | 0.116 |
| CHB | 39(11.3) | 6(18.8) | 42(14.1) | 0.227 |
| RCC | 14(4.1) | 4(12.5) | 18(6.1) | |
| Others | 8(2.3) | 0 | 5(1.7) |
P value < 0.05 will be bold. Data are presented as n (%). Continuous variables are presented as mean ± standard deviation
MMs, missense mutations; oTR, other truncating mutations; del, deletion; SD, standard deviation; CHB, central nervous system hemangioblastoma; RA, retinal anginoma; RCC, renal cell carcinoma; PHEO, pheochromocytoma; PCT, pancreatic cyst or tumor
Fig. 3.
Comparison of age-related risks in Codon 65 MMs, oHMs and nHMs. a All the five VHL-associated tumor, b CHB, c RA, d RCC, e PCT, f PHEO. MMs, missense mutations; oMMs, other codons missense mutations; oHM, other Hifα-binding site missense mutations; nΗM, non-Hifα-binding site missense mutations; CHB, central nervous system hemangioblastoma; RA, retinal anginoma; RCC, renal cell carcinoma; PHEO, pheochromocytoma; PCT, pancreatic cyst or tumor
Table 4.
Clinical and mutational characteristics of patients with MMs, c.481C > T and oTR(481)
| MMs | c.481C > T | oTR(481) | P value | |
|---|---|---|---|---|
| Patients | 345 | 23 | 306 | |
| Unrelated families | 138 | 15 | 129 | |
| Sex, n(%) | 0.829 | |||
| Male | 200(58.0) | 12(52.2) | 173(56.5) | |
| Female | 145(42.0) | 11(47.8) | 133(43.5) | |
| Age (mean ± SD) | 38.3 ± 14.8 | 37.9 ± 14.8 | 38.2 ± 14.7 | 0.564 |
| Clinical type, n(%) | < 0.001 | |||
| Type 1 | 253(73.3) | 20(87.0) | 285(93.1) | |
| Type 2 | 92(26.7) | 3(13.0) | 21(6.9) | |
| Onset age, n(%) | 0.668 | |||
| ≤ 30 years | 159(46.1) | 14(60.9) | 151(49.3) | |
| > 30 years | 152(44.1) | 7(30.4) | 125(40.8) | |
| Asymptomatic | 34(9.8) | 2(8.7) | 30(9.8) | |
| Affected lesion, n(%) | ||||
| CHB | 201(58.3) | 20(87.0) | 214(69.9) | 0.001 |
| RA | 55(15.9) | 6(26.1) | 76(24.8) | 0.015 |
| RCC | 154(44.6) | 17(73.9) | 155(50.7) | 0.014 |
| PHEO | 92(26.7) | 3(13.0) | 21(6.9) | < 0.001 |
| PCT | 161(46.7) | 17(73.9) | 147(48.0) | 0.040 |
| Death and cause, n(%) | ||||
| Death (any cause) | 61(17.7) | 1(4.3) | 74(24.2) | 0.019 |
| CHB | 39(11.3) | 1(4.3) | 47(15.4) | 0.119 |
| RCC | 14(4.1) | 0 | 22(7.2) | |
| Others | 8(2.3) | 0 | 5(1.6) |
Data are presented as n (%). Continuous variables are presented as mean ± standard deviation
MMs, missense mutations; oTR, other truncating mutations; SD, standard deviation; CHB, central nervous system hemangioblastoma; RA, retinal anginoma; RCC, renal cell carcinoma; PHEO, pheochromocytoma; PCT, pancreatic cyst or tumor
P value < 0.05 will be bold
Table 5.
Clinical and mutational characteristics of patients with MMs, c.224-226del and oTR(224-226)
| MMs | c.224-226del | oTR(224-226) | P value | |
|---|---|---|---|---|
| Patients | 345 | 28 | 301 | |
| Unrelated families | 138 | 10 | 134 | |
| Sex, n(%) | 0.896 | |||
| Male | 200(58.0) | 16(57.1) | 169(56.1) | |
| Female | 145(42.0) | 12(42.9) | 132(43.9) | |
| Age (mean ± SD) | 38.3 ± 14.8 | 37.1 ± 14.8 | 38.2 ± 14.7 | 0.717 |
| Clinical type, n(%) | < 0.001 | |||
| Type 1 | 253(73.3) | 28(100) | 277(92.0) | |
| Type 2 | 92(26.7) | 0 | 24(8.0) | |
| Onset age, n(%) | 0.576 | |||
| ≤ 30 years | 159(46.1) | 11(39.3) | 154(51.2) | |
| > 30 years | 152(44.1) | 13(46.4) | 119(39.5) | |
| Asymptomatic | 34(9.8) | 4(14.3) | 28(9.3) | |
| Affected lesion, n(%) | ||||
| CHB | 201(58.3) | 21(75.0) | 213(70.8) | 0.002 |
| RA | 55(15.9) | 3(10.7) | 79(26.2) | 0.002 |
| RCC | 154(44.6) | 9(32.1) | 163(54.2) | 0.012 |
| PHEO | 92(26.7) | 0 | 24(8.0) | < 0.001 |
| PCT | 161(46.7) | 5(17.9) | 159(52.8) | 0.001 |
| Death and cause, n(%) | ||||
| Death (any cause) | 61(17.7) | 11(39.3) | 64(21.3) | 0.019 |
| CHB | 39(11.3) | 10(35.7) | 38(12.6) | 0.008 |
| RCC | 14(4.1) | 1(3.6) | 21(7.0) | |
| Others | 8(2.3) | 0 | 5(1.7) |
Data are presented as n (%). Continuous variables are presented as mean ± standard deviation
MMs, missense mutations; oTR, other truncating mutations; SD, standard deviation; CHB, central nervous system hemangioblastoma; RA, retinal anginoma; RCC, renal cell carcinoma; PHEO, pheochromocytoma; PCT, pancreatic cyst or tumor
P value < 0.05 will be bold
Exon 2 deletion was characterised by higher RA risk and unfavourable RCC-specific survival
As a major subtype of copy number variation, exon 2 deletion was characterised by a significantly higher prevalence of RA than missense mutations or other truncation mutations (40.6% vs. 15.9% vs. 23.2%, P = 0.001; Table 3). Cox regression analysis showed that exon 2 deletion conferred a significantly increased age-related risk of RA (HR, 2.787; 95% CI 1.522–5.102; P = 0.001; Supplement Table 6). Moreover, patients with exon 2 deletion had an earlier age of RA onset (P = 0.011; Fig. 4). In contrast, similar to truncation mutations, exon 2 deletion was associated with a lower prevalence (9.4% vs. 7.1% vs. 26.7%, P < 0.001) and age-related risk of pheochromocytoma (HR, 0.313; 95% CI 0.099–0.990; P = 0.048; Table 3; Supplement Table 6).
Fig. 4.
Comparison of age-related risks in MMs, Exon2 del and oTR(Exon2 del). a All the five VHL-associated tumor, b CHB, c RA, d RCC, e PCT, f PHEO. MMs, missense mutations; oTR, other truncating mutations; del, deletion; CHB, central nervous system hemangioblastoma; RA, retinal anginoma; RCC, renal cell carcinoma; PHEO, pheochromocytoma; PCT, pancreatic cyst or tumor
Given these phenotypic patterns, we evaluated the clinical outcomes associated with exon 2 deletion. Although no significant differences were found in RCC prevalence, age at onset, or RCC-specific survival in the unadjusted analyses (Fig. 4; Supplement Fig. 3; Supplement Table 6), multivariate Cox regression analysis identified exon 2 deletion as an independent risk factor for RCC-specific survival (HR, 3.406; 95% CI 1.111–10.441; P = 0.032; Supplement Table 7).
c.481C > T was associated with increased risks of multiple VHL-related lesions
As a subtype of nonsense mutations, c.481C > T (p.Arg161*) was characterised by a greater burden of VHL-related lesions. Compared with patients carrying missense mutations and other truncation mutations, those with c.481C > T had a significantly higher prevalence of CHB (87.0% vs. 58.3% vs. 69.9%, P = 0.001), RCC (73.9% vs. 44.6% vs. 50.7%, P = 0.014), and PCT (73.9% vs. 46.7% vs. 48.0%, P = 0.040; Table 4). Cox regression analyses demonstrated that c.481C > T was associated with significantly increased age-related risks of CHB (HR, 2.257; 95% CI 1.421–3.583; P = 0.001), RCC (HR, 2.272; 95% CI 1.370–3.768; P = 0.001), and PCT (HR, 2.130; 95% CI 1.287–3.523; P = 0.003; Supplement Table 8; Fig. 5).
Fig. 5.
Comparison of age-related risks in MMs, c.481C > T and oTR(481). a All the five VHL-associated tumor, b CHB, c RA, d RCC, e PCT, f PHEO. MMs, missense mutations; oTR, other truncating mutations; CHB, central nervous system hemangioblastoma; RA, retinal anginoma; RCC, renal cell carcinoma; PHEO, pheochromocytoma; PCT, pancreatic cyst or tumor
We further assessed the prognostic significance of c.481C > T. However, no significant differences were observed in survival outcomes, and no independent prognostic factors were identified in this subgroup (Supplement Table 9; Supplement Fig. 4). This negative finding may be attributable to the limited number of endpoint events, which may have reduced the statistical power of the survival analysis.
c.224-226del was characterised by a distinct CHB-predominant phenotype
The c.224-226del mutation was the predominant subtype among the small indels. Compared with those carrying missense mutations and other truncation mutations, patients harbouring c.224-226del showed a significantly higher incidence of CHB (75.0% vs. 58.3% vs. 70.8%, P = 0.002) but a significantly lower incidence of PCT (17.9% vs. 46.7% vs. 52.8%, P = 0.001). Moreover, patients with c.224-226del had a significantly higher overall mortality rate (39.3% vs. 17.7% vs. 21.3%, P = 0.019), and 10 patients (35.7%) died from CHB (Table 5).
Cox regression analysis demonstrated that c.224-226del was associated with a lower age-related risk of PCT (HR, 0.384; 95% CI 0.158–0.936; P = 0.035; Supplement Table 10). Although patients with c.224-226del developed CHB at a younger age (Fig. 6), this mutation was not identified as an independent risk factor for age-related CHB risk or CHB-specific survival (Supplement Table 10; Supplement Table 11; Supplement Fig. 5), suggesting that the observed difference may be influenced by other clinical factors.
Fig. 6.
Comparison of age-related risks in MMs, c.224-226del and oTR(224–226). a All the five VHL-associated tumor, b CHB, c RA, d RCC, e PCT, f PHEO. MMs, missense mutations; oTR, other truncating mutations; CHB, central nervous system hemangioblastoma; RA, retinal anginoma; RCC, renal cell carcinoma; PHEO, pheochromocytoma; PCT, pancreatic cyst or tumor
Discussion
VHL disease is a multisystem tumour syndrome with unfavourable clinical outcomes; it is characterised by marked inter- and intrafamilial heterogeneity in tumour spectrum, age at onset, and prognosis (Lomte et al. 2018; Lee et al. 2025). Owing to the rarity of this disease, recruiting sufficiently large cohorts for robust genotype–phenotype analyses is difficult, and improvements in mutation-specific risk stratification have been limited in clinical practice. Currently, the conventional classification of VHL disease is largely based on the penetrance of pheochromocytoma, dividing patients into types 1 and 2 (Nielsen et al. 2016; Li et al. 2022). Although this classification has important historical and clinical value, it is insufficient for individualised surveillance and management of the wide spectrum of VHL-associated tumours. Our groups have previously reported the genotype–phenotype correlations in Chinese patients with VHL disease, most prior analyses were based on broad mutation categories, functional domains, or selected organ-specific manifestations (Qiu et al. 2020). The clinical relevance of recurrent hotspot mutation subtypes has not been systematically evaluated. Our previous study showed that mutations in codons 80 or 167 conferred significantly higher risks of pheochromocytoma than other VHL mutations (Peng et al. 2017), suggesting that a classification strategy based on specific mutation subtypes may provide more clinically meaningful information than the conventional framework. Building on this concept, the present study enrolled 674 patients with VHL syndrome from 283 unrelated families. The present study focuses on recurrent hotspot mutation subtypes, including codon 65 missense variants, exon 2 deletion, c.481C > T (p.Arg161*), and c.224_226del. These four recurrent subtypes were analysed separately rather than being grouped only into broad categories such as missense or truncating variants. We further evaluated mutation-specific tumour spectra, age-related tumour risks, and survival outcomes, aiming to provide a more precise mutation subtype–based risk stratification framework. Our findings refine the traditional genotype–phenotype correlations in VHL disease and support the notion that recurrent mutation subtypes are associated with distinct clinical patterns (Fig. 7). These results (covering 19.6% of patients with VHL syndrome) contribute to a more precise risk stratification and provide a stronger basis for mutation-guided surveillance and individualised management of patients with VHL disease.
Fig. 7.
Schematic diagram of precise VHL hotspot mutation stratification. CHB, central nervous system hemangioblastoma; RA, retinal anginoma; RCC, renal cell carcinoma; PHEO, pheochromocytoma; PCT, pancreatic cyst or tumor. Created with Biorender.com
The VHL protein (pVHL) is a critical component of the E3 ubiquitin ligase complex and contains multiple functional domains that mediate substrate recognition and protein–protein interactions. The β-domain of pVHL, which comprises several β-sheets, is responsible for binding HIF-α with residues 65–117 (Ma et al. 2022). Previous studies have shown that the risk of pheochromocytoma is lower in patients with missense mutations located in the HIF-α binding site than in those with missense mutations outside this region, suggesting that different missense mutations may exert distinct biological effects depending on their structural location and functional consequences (Liu et al. 2018). In the present study, we expanded upon this observation by showing that codon 65 mutations, the most frequent subtype within the HIF-α binding site missense group, were associated with a significantly lower prevalence of pheochromocytoma than other mutation types. In addition, both the prevalence and age-related risk of RA were significantly reduced in patients carrying codon 65 mutations, indicating that this subtype is associated with a relatively milder clinical phenotype.
A possible explanation for this finding is that codon 65 missense mutations may not completely disrupt the function of pVHL. Beyond HIF-α, an increasing number of HIF-independent substrates, regulated by pVHL, have been identified in recent years, including TANK binding kinase 1 (TBK1) and zinc fingers and homeoboxes 2 (ZHX2), all of which play important roles in tumour initiation and progression (Hu et al. 2020; Zhang et al. 2018). Moreover, recent studies have identified novel somatic and germline mutations in EPAS1 (HIF2A) as the cause of a syndrome characterised by multiple and recurrent pheochromocytomas/paragangliomas and polycythaemia, further supporting the critical role of HIF-2α pathway activation in the pathogenesis of these lesions (Bechmann et al. 2024; Alzahrani et al. 2024). Therefore, the relatively mild phenotype observed in patients with codon 65 missense mutations may result from the partial preservation of pVHL-mediated HIF-α degradation. This finding suggests that codon 65 may represent a relatively functionally tolerant or structurally stable region of pVHL in which amino acid substitutions are less likely to produce severe functional impairment, thereby resulting in lower tumour penetrance and a comparatively attenuated clinical course.
Traditionally, VHL truncation mutations have been broadly classified as type 1 mutations and are generally considered to be associated with a lower risk of pheochromocytoma (Nielsen et al. 2016). However, our findings suggest that this conventional grouping may obscure substantial heterogeneity among the different truncation mutation subtypes. In the present study, the three recurrent truncation mutation subtypes analysed (exon 2 deletion, c.481C > T, and c.224_226del) shared certain common features but also exhibited distinct phenotypic characteristics, highlighting the clinical importance of mutation-specific classification.
Among these truncation mutations, exon 2 deletion was characterised by a significantly higher prevalence of RA, earlier age at RA onset, and increased age-related risk of RA, whereas the prevalence and age-related risk of pheochromocytoma were reduced. In addition, although no significant association with RCC-specific survival was observed in the univariate analysis, multivariate Cox regression analysis identified exon 2 deletion as an independent adverse factor for RCC-specific survival. These findings may be partially explained by the unique biological consequences of exon 2 deletion. Previous studies have shown that exon 2 deletion gives rise to the pVHL172 isoform (Baldini et al. 2017; Chesnel et al. 2015). Partial loss of the β-domain in this isoform, particularly residues 114–154, alters the number of β-sheets within the protein, which may affect protein folding and influence its activity and protein–protein interaction network (Minervini et al. 2019). Other studies have suggested that this region is involved in pVHL intracellular localisation, ribosome biogenesis, protein synthesis, and tumour initiation or progression (Li et al. 2022, 2026; Schoenfeld et al. 2000). Therefore, structural and functional disruptions caused by exon 2 deletion may underlie the increased RA susceptibility and unfavourable RCC-related outcomes observed in our cohort.
In contrast, c.481C > T, a nonsense mutation affecting the Elongin C binding region (amino acids 155–192), was associated with a broader and more severe disease burden (Mu et al. 2023; Andreou et al. 2022). This region is critical for binding Elongin C and for assembly of the VCB-CUL2 E3 ubiquitin ligase complex. Previous studies have suggested that missense mutations in this region may serve as independent protective factors for age-related CHB risk, overall survival, and CHB-specific survival in patients with VHL disease, indicating that different mutation types within the same functional domain may exert different biological effects (Xie et al. 2020). However, in our study, c.481C > T was associated with significantly increased prevalences and age-related risks of CHB, RCC, and PCT, although no independent effect on survival outcomes was observed. This discrepancy may reflect the more profound structural and functional impairments caused by a truncation mutation compared with a missense mutation within the same region.
Notably, c.224_226del, a frameshift mutation, affects both the HIF-α and Elongin C binding regions and was associated with a distinct CHB-predominant phenotype in our cohort. Patients harbouring this mutation had a higher incidence of CHB, earlier CHB onset, and lower prevalence and age-related risk of PCT. Moreover, they had a significantly higher overall mortality rate, with a considerable proportion of deaths attributed to CHB. Nevertheless, c.224_226del was not identified as an independent predictor of age-related CHB risk or CHB-specific survival in the multivariate analyses. CHB is one of the most common lesions in patients with VHL disease, and accumulating evidence suggests that HIF-related vascular tumours, including CHB, RA, and RCC, are at least partly driven by dysregulation of the VHL-HIF signalling pathway (Liu et al. 2018; Toledo et al. 2023). Compared with missense mutations, truncation mutations often result in the loss of larger amino acid fragments and are therefore more likely to cause substantial disruption of pVHL structure and function. Therefore, truncation mutations may more readily impair the VHL-HIF pathway and promote the development of highly vascular tumours, which is consistent with the phenotype observed in c.224_226del carriers.
The major strength of this study lies in its use of the largest VHL patient database and biobank currently available in China. To the best of our knowledge, this is the first study to systematically investigate the clinical phenotypes and possible biological implications of several recurrent hotspot mutation subtypes in a large Chinese VHL cohort. Our findings indicate that codon 65 missense mutations are associated with a relatively milder clinical phenotype and favourable prognosis, whereas exon 2 deletion, c.481C > T, and c.224_226del are associated with a heavier disease burden and may therefore benefit more from clinical surveillance, management, and genetic counselling. In this regard, our study further expands the current understanding of genotype–phenotype correlations in VHL disease and provides evidence supporting a more refined mutation subtype–based classification framework. Several hotspot variants identified in the present cohort appeared to be recurrent among Chinese patients with VHL disease. These variants may represent population-enriched recurrent mutations and could potentially include Chinese founder variants. However, the present study was not designed to prove a founder effect, as haplotype analysis, ancestry-based segregation analysis, and population-level genetic data were not available. Therefore, we have avoided overinterpreting these recurrent variants as confirmed founder variants. Future multicentre studies incorporating haplotype analysis and broader population genetic data are needed to determine whether these recurrent variants represent true Chinese founder variants or mutational hotspots.
However, several limitations should also be acknowledged. First, this study focused primarily on recurrent hotspot mutation subtypes, and other pathogenic variants were not analysed in detail. As the sample size continues to increase, future studies should investigate additional mutation sites and explore the molecular mechanisms underlying VHL-associated tumourigenesis. Second, this was a single-centre retrospective cohort study, a design that has inherent selection and information biases. Consequently, large multicentre prospective studies are required to validate our findings and assess their generalisability.
Conclusion
This study augments the existing genotype–phenotype research on VHL disease. Our findings suggest that specific mutation subtypes may serve as valuable references for clinical decision-making and genetic counselling. More importantly, these results support a shift from a broad mutation category–based classification to a more individualised, fine-scale mutation subtype–oriented strategy, which may ultimately facilitate personalised diagnosis, surveillance, and treatment in patients with VHL disease.
Supplementary Information
Below is the link to the electronic supplementary material.
Supplementary file1. Comparison of survival in Codon 65 MMs , oMMs and TR. Overall survival in patients with different mutations (b) CHB-specific survival in patients with different mutations (c) RCC-specific survival in patients with different mutations. MMs, missense mutations; oMMs, other codons missense mutations; TR, truncating mutations; CHB, central nervous system hemangioblastoma; RCC, renal cell carcinoma
Supplementary file2. Comparison of survival in Codon 65 MMs, oHMs and nHM. (a) Overall survival in patients with different mutations (b) CHB-specific survival in patients with different mutations (c) RCC-specific survival in patients with different mutations. MMs, missense mutations; oHM, other HIFα-binding site missense mutations; nEM, non-HIFα-binding site missense mutations; CHB, central nervous system hemangioblastoma; RCC, renal cell carcinoma
Supplementary file3. Comparison of survival in Exon2 del, oTR(Exon2) and MMs. (a) Overall survival in patients with different mutations (b) CHB-specific survival in patients with different mutations (c) RCC-specific survival in patients with different mutations. MMs, missense mutations; oTR, other truncating mutations; del, deletion; CHB, central nervous system hemangioblastoma; RCC, renal cell carcinoma
Supplementary file4. Comparison of survival in c.481C>T , oTR(481) and MMs. (a)Overall survival in patients with different mutations (b) CHB-specific survival in patients with different mutations (c) RCC-specific survival in patients with different mutations. MMs, missense mutations; oTR, other truncating mutations; CHB, central nervous system hemangioblastoma; RCC, renal cell carcinoma
Supplementary file5. Comparison of survival in c.224-226del, oTR(224-226) and MMs. (a)Overall survival in patients with different mutations (b) CHB-specific survival in patients with different mutations (c) RCC-specific survival in patients with different mutations. MMs, missense mutations; oTR, other truncating mutations; CHB, central nervous system hemangioblastoma; RCC, renal cell carcinoma
Author contributions
Conceptualisation: KG, YW, JZ and CW. Data curation: CW, JQ and TL. Formal analysis: CW, JQ and TL. Funding acquisition: KG, YW, JZ. Investigation: YB. Software: CW. Methodology: CW, JQ and TL. Visualisation: CW, JQ and TL. Writing the original draft: CW, JQ and TL. Writing the review and editing: KG, YW, JZ and CW. KG is the guarantor.
Funding
This work was supported by the National High Level Hospital Clinical Research Funding (Scientific and Technological Achievements Transformation Incubation Guidance Fund Project of Peking University First Hospital, 2024CX23; Youth Clinical Research Project of Peking University First Hospital, 2024YC03), Noncommunicable Chronic Disease-National Science and Technology Major Project (No. 2026ZD0553703), the National Natural Science Foundation of China (No. 82503940) and the Beijing Natural Science Foundation (No. L258066).
Data availability
No datasets were generated or analysed during the current study.
Declarations
Conflict of interest
The authors declare no competing interests.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Chuandong Wang, Jianhui Qiu, and Tao Liu have contributed equally to this work.
Contributor Information
Jingcheng Zhou, Email: zhjc1021@126.com.
Yizhou Wang, Email: yizhouwang@bjmu.edu.cn.
Kan Gong, Email: kan.gong@bjmu.edu.cn.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary file1. Comparison of survival in Codon 65 MMs , oMMs and TR. Overall survival in patients with different mutations (b) CHB-specific survival in patients with different mutations (c) RCC-specific survival in patients with different mutations. MMs, missense mutations; oMMs, other codons missense mutations; TR, truncating mutations; CHB, central nervous system hemangioblastoma; RCC, renal cell carcinoma
Supplementary file2. Comparison of survival in Codon 65 MMs, oHMs and nHM. (a) Overall survival in patients with different mutations (b) CHB-specific survival in patients with different mutations (c) RCC-specific survival in patients with different mutations. MMs, missense mutations; oHM, other HIFα-binding site missense mutations; nEM, non-HIFα-binding site missense mutations; CHB, central nervous system hemangioblastoma; RCC, renal cell carcinoma
Supplementary file3. Comparison of survival in Exon2 del, oTR(Exon2) and MMs. (a) Overall survival in patients with different mutations (b) CHB-specific survival in patients with different mutations (c) RCC-specific survival in patients with different mutations. MMs, missense mutations; oTR, other truncating mutations; del, deletion; CHB, central nervous system hemangioblastoma; RCC, renal cell carcinoma
Supplementary file4. Comparison of survival in c.481C>T , oTR(481) and MMs. (a)Overall survival in patients with different mutations (b) CHB-specific survival in patients with different mutations (c) RCC-specific survival in patients with different mutations. MMs, missense mutations; oTR, other truncating mutations; CHB, central nervous system hemangioblastoma; RCC, renal cell carcinoma
Supplementary file5. Comparison of survival in c.224-226del, oTR(224-226) and MMs. (a)Overall survival in patients with different mutations (b) CHB-specific survival in patients with different mutations (c) RCC-specific survival in patients with different mutations. MMs, missense mutations; oTR, other truncating mutations; CHB, central nervous system hemangioblastoma; RCC, renal cell carcinoma
Data Availability Statement
No datasets were generated or analysed during the current study.