Genotype-phenotype correlations in families with deletions in the von Hippel-Lindau (VHL) gene

Von Hippel-Lindau (VHL) disease is a hereditary tumor syndrome characterizc d by predisposition for bilateral and multi-centric hemangioblastoma in the retina and central nervous system, pheochromocytoma, renal cell carcinoma, and cysts in the kidney, pancreas, and epididymis. We describe five famili es for which direct sequencing of the coding region of the VHL gene had fai led to identify the family-specific mutation. Further molecular analysis re vealed deletions involving the VHL gene in each of these families. III four families, partial deletions of one or more exons were detected by Southern blot analysis. In the fifth family, FISH analysis demonstrated the deletio n of the entire VHL gene. Our results show that (quantitative) Southern blo t analysis is a sensitive method for detecting germline deletions of the VH L gene and should be implemented in routine DNA diagnosis for VHL disease. Our data support the previously established observation that families with a germline deletion have a low risk for pheochromocytoma. Further unravelin g of genotype-phenotype correlations in VHL disease has revealed that famil ies with a full or partial deletion of the VHL gene exhibit a phenotype wit h a preponderance of central nervous system hemangioblastoma.