Von Hippel Lindau disease (VHL) is a hereditary syndrome, associated with
tumors and
cysts in multiple organ systems, whose expression and age of onset are highly variable. The availability of a genetic test for the early and reliable detection of individuals carrying the defective gene would be beneficial for VHL patients and their relatives, since many of the manifestations of VHL can be successfully treated if detected in their early stages, while the complications of undetected disease can be devastating. We have previously shown that the VHL gene maps to chromosome 3p. To provide
genetic markers for the development of a reliable diagnostic test, and to further narrow and eventually clone the VHL defect, we have generated
DNA markers for chromosome 3p. With these markers, we have performed a multipoint genetic linkage analysis in 28 VHL pedigrees, comprising 470 individuals, 164 of whom were affected with VHL. Here we report the identification of tightly linked markers, including flanking markers that bracket the VHL gene to a small region on chromosome 3p25-p26. This finding has several major implications. While visceral
cysts of the kidney, pancreas, and epididymis are commonly found in VHL and are considered diagnostic criteria for this disorder, they also occur in the general population. The presence of
cysts, unaccompanied by other more typical lesions such as
retinal and cerebellar
hemangioblastoma, may therefore represent a major diagnostic problem, leading to errors in the assessment of disease status. The application of flanking markers for the VHL gene for presymptomatic diagnostic testing confirms that
epididymal cysts are indeed not suitable as a diagnostic criterion in this disorder.
Pheochromocytomas occur nonuniformly in VHL families and may also be associated with other hereditary
tumor syndromes; our genetic studies imply that the phenotype in VHL families with and without
pheochromocytomas is caused by defects within the same gene. The absence or presence of this
tumor type is therefore due to the pleiotropic expression of a single gene rather than to the existence of several different genes for VHL. The region on chromosome 3p13-p14 known to contain several
chromosomal translocation breakpoints in families with "pure
familial renal cell carcinoma" is quite proximal to the VHL locus in 3p25-p26 we have identified. Chromosome 3p may therefore contain two loci for
renal cell carcinoma: one gene (or genes) in 3p13-p14 and the VHL gene in 3p25-p26, whose aberration is also associated with other typical manifestations of VHL. Since
renal cell carcinoma,
pheochromocytoma, and visceral
cysts can occur sporadically even in young people and may also be associated with other
tumor syndromes, the availability of flanking markers for the VHL gene will be useful in identifying VHL gene carriers, particularly among those individuals at risk in whom these are the only manifestations of disease. The isolation and characterization of the VHL gene, based on the identification of flanking markers, will have important implications for diagnosis and treatment of patients with VHL, as well as for a much larger number of individuals having the sporadic counterparts of VHL-associated
tumor types.