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Abstract
Von Hippel–Lindau (VHL) disease is a rare autosomal-dominant inherited tumor syndrome. We aimed to analyze the correlations between frequent VHL mutations and phenotypes in Chinese VHL families. We screened 540 patients from 187 unrelated Chinese VHL families for 19 frequent VHL mutations. The penetrance and mean age at onset for VHL-associated susceptible organs were calculated and compared. The overall survival of VHL patients was described with Kaplan–Meier curves. Among the 19 frequent germline mutations, there were four hotspot mutation sites (194, 481, 499, and 500). Missense mutations were the most common types of mutations (70.0%) followed by nonsense mutations (20.0%) and splicing mutations (10.0%). Due to the diversity of these mutations, the penetrance for each organ and the age at onset are distinct. Even in cases of similar mutations, variance in the penetrance and age at onset was observed. The mean age at death for the patients in this cohort was 42.4 ± 13.5 years, and variability was observed in the Kaplan–Meier curves. We present a precise summary of the phenotypes for the frequent VHL mutations in the largest Chinese VHL cohort, which provides valuable strategies for genetic counseling and clinical surveillance of VHL individuals.
Highlights
Von Hippel–Lindau (VHL) disease (OMIM no. 193300) is an autosomal-dominant familial neoplastic condition that is caused by germline mutations in the VHL gene located on chromosome 3p25-26
A follow-up was performed on all patients and asymptomatic carriers in the VHL families to determine the age at onset for six major VHL-related lesions: central nervous system hemangioblastoma (CHB), retinal angioma (RA), RCC, pancreatic tumor or cyst (PCT), PHEO, and GS
A total of 540 patients from 187 unrelated Chinese VHL families were included in our database, and 126 different types of VHL mutations were identified
Summary
Von Hippel–Lindau (VHL) disease (OMIM no. 193300) is an autosomal-dominant familial neoplastic condition that is caused by germline mutations in the VHL gene located on chromosome 3p25-26. 193300) is an autosomal-dominant familial neoplastic condition that is caused by germline mutations in the VHL gene located on chromosome 3p25-26. This gene comprises three exons: exon 1 spans nucleotides 1–340 (codons 1–113), exon 2 spans nucleotides 341–463 (codons 114–154), and exon 3 spans nucleotides 464–642 (codons 155–213) (Latif et al, 1993; Nielsen et al, 2016; Varshney et al, 2017). Individuals with a family history of VHL will be clinically diagnosed when he/she presents with VHL-associated tumors that include CHB, RA, or RCC (Chittiboina and Lonser, 2015). The detection of VHL mutations contributes to an early and precise diagnosis of at-risk individuals and helps to elucidate the genotype–phenotype correlations within a given population
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