title: Genotype-phenotype correlations in Chinese von Hippel-Lindau disease patients.
abstract: von Hippel-Lindau (VHL) disease is caused by mutations in the VHL gene and demonstrates marked phenotypic variability. Genotype-phenotype correlations in Chinese VHL patients have been unclear. To establish genotype-phenotype correlations in Chinese VHL patients, we collected VHL mutations and phenotypes of 291 patients with VHL disease from 115 unrelated families. Genotype-phenotype correlations at mutation type level, mutation region level, and mutation codon level were analyzed by Kaplan-Meier curves and Cox regression models. We found missense mutations conferred an increased risk of pheochromocytoma developments, but a decreased risk of central nervous system hemangioblastomas (CHBs) and pancreatic lesions. Patients with VHL deletions were more prone to developing retinal angiomas. Renal cell carcinomas were more frequent in nonsense, frameshift or splice-site mutations. Mutations in Exon 2 conferred a higher risk and earlier diagnostic age of CHBs than mutations in other exons (HR = 1.684, 95% CI 1.082-2.620, p = 0.021; 27.0 ± 9.7 years versus 32.8 ± 11.7 years, p = 0.024), while patients with mutations in Exon 3 were more prone to developing pheochromocytomas (HR = 2.760, 95% CI 1.419-5.370, p = 0.003). Mutations at codon 80 or codon167 conferred significantly higher risks of pheochromocytomas than other mutations (HR = 4.678, 95% CI 1.392-15.724, p = 0.013; HR = 4.683, 95% CI 2.515-8.719, p < 0.001 respectively). In conclusion, VHL mutation types, mutation regions and mutation codons can act as phenotypic predictors of VHL disease. Mutation regions and mutation codons may aid in directed surveillance and monitoring of VHL patients.
authors.affiliation: Department of Urology, Peking University First Hospital, Beijing, P.R China.|Institute of Urology, Peking University, Beijing, P.R China.|National Urological Cancer Center, Beijing, P.R China.
authors.forename: Shuanghe
authors.initials: S
authors.lastname: Peng
authors.affiliation: Department of Neurological Surgery, University of Virginia, Charlottesville, Virginia, USA.|Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Shepard
authors.affiliation: Department of Urology, Peking University First Hospital, Beijing, P.R China.|Institute of Urology, Peking University, Beijing, P.R China.|National Urological Cancer Center, Beijing, P.R China.
authors.forename: Jiangyi
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Urology, Peking University First Hospital, Beijing, P.R China.|Institute of Urology, Peking University, Beijing, P.R China.|National Urological Cancer Center, Beijing, P.R China.
authors.forename: Teng
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of Urology, Peking University First Hospital, Beijing, P.R China.|Institute of Urology, Peking University, Beijing, P.R China.|National Urological Cancer Center, Beijing, P.R China.
authors.forename: Xianghui
authors.initials: X
authors.lastname: Ning
authors.affiliation: Department of Urology, Peking University First Hospital, Beijing, P.R China.|Institute of Urology, Peking University, Beijing, P.R China.|National Urological Cancer Center, Beijing, P.R China.
authors.forename: Lin
authors.initials: L
authors.lastname: Cai
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Zhuang
authors.affiliation: Department of Urology, Peking University First Hospital, Beijing, P.R China.|Institute of Urology, Peking University, Beijing, P.R China.|National Urological Cancer Center, Beijing, P.R China.
authors.forename: Kan
authors.initials: K
authors.lastname: Gong
mesh_terms: D000328:Adult; D017668:Age of Onset; D044466:Asian People / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics; D006623:von Hippel-Lindau Disease / Q000235:genetics* / Q000473:pathology*
chemical_list: D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human
keywords: VHL; VHL mutation; genotype-phenotype correlation; phenotypic predictor; von Hippel–Lindau