Associations between VHL genotype and clinical phenotype in familial von Hippel-Lindau disease

Background Von Hippel-Lindau (VHL) disease is an autosomal dominant hereditary disorder associated with tumours and cysts in the central nervous system (CNS) and other visceral organs. Germline mutations in the VHL gene on chromosome 3p25-26 are considered the cause of this disease. Materials and methods We studied six patients with VHL disease and their relatives. Loss of heterozygosity (LOH) was determined by five flanking microsatellite polymorphic markers in the VHL locus. Multiplex ligation-dependent probe amplification (MLPA) and quantitative real-time polymerase chain reaction (qPCR) amplification were used to detect the genomic deletions. Single-strand conformation polymorphism (SSCP) analysis was applied to test for sequence variations. Results Three germline deletions in the VHL gene (142.9, 53.3 and 3.3 kb) were found by MLPA. These deletions were defined clearly by qPCR analyses. The142.9 kb germline deletion was significantly associated with patients with CNS haemangioblastomas (P < 0.01 by Fisher's exact test), and one missense mutation (Gln209Arg) was detected from a patient with a pancreatic cyst in the same family. LOH was also detected from a patient with bilateral renal cell carcinomas. Conclusion Diverse genetic conditions are associated with the clinical manifestations of VHL disease. Genomic deletions that can be detected by MLPA or qPCR are major causes for this syndrome. Missense mutations and LOH accompanying the disease lead to complex clinical symptoms and genotypic determination can facilitate a clinical diagnosis because of their strong association.