title: Genotype-phenotype correlations in VHL exon deletions.
abstract: Von Hippel-Lindau (VHL) syndrome is a dominantly inherited familial cancer syndrome caused by mutations in the VHL gene. VHL syndrome displays marked variation in expression and analysis of genotype-phenotype correlations have led to the concept of four subtypes of VHL syndrome (Types 1, 2A-C). Type 2 subtypes of VHL syndrome are characterized by the presence of pheochromocytoma and the three Type 2 subtypes are associated with differing risks of hemangioblastoma and renal cell carcinoma (RCC). Type 2 VHL syndrome is usually associated with surface missense mutations. Type 1 VHL syndrome is most commonly caused by germline exon deletions and truncating mutations and is characterized by susceptibility to hemangioblastomas and RCC but not pheochromocytoma. Recently, it has been suggested that large VHL gene deletions involving C3orf10 (HSPC300) might be associated with a low risk of RCC. We have reviewed the molecular and clinical characteristics of 127 individuals with germline VHL gene deletions. Large VHL gene deletions associated with a contiguous loss of C3orf10 were associated with a significantly lower lifetime risk of RCC than deletions that did not involve C3orf10. The risks of hemangioblastomas were similar in both groups. These results add to the growing body of evidence suggesting that patients with VHL syndrome caused by large VHL deletions that include C3orf10 may be designated as having a specific subtype (Type 1B) of the disorder.
authors.affiliation: Department of Medical and Molecular Genetics, Institute of Biomedical Research, University of Birmingham, Birmingham, UK.
authors.forename: Alisdair
authors.initials: A
authors.lastname: McNeill
authors.forename: Eleanor
authors.initials: E
authors.lastname: Rattenberry
authors.forename: Richard
authors.initials: R
authors.lastname: Barber
authors.forename: Pip
authors.initials: P
authors.lastname: Killick
authors.forename: Fiona
authors.initials: F
authors.lastname: MacDonald
authors.forename: Eamonn R
authors.initials: ER
authors.lastname: Maher
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000150:complications / Q000235:genetics; D002292:Carcinoma, Renal Cell / Q000150:complications / Q000235:genetics; D002528:Cerebellar Neoplasms / Q000150:complications / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000235:genetics; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics; D017353:Gene Deletion; D005838:Genotype; D018095:Germ-Line Mutation; D018325:Hemangioblastoma / Q000150:complications / Q000235:genetics; D006801:Humans; D007680:Kidney Neoplasms / Q000150:complications / Q000235:genetics; D010641:Phenotype; D010673:Pheochromocytoma / Q000150:complications / Q000235:genetics; D019572:Retinal Neoplasms / Q000150:complications / Q000235:genetics; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*; D006623:von Hippel-Lindau Disease / Q000145:classification* / Q000150:complications / Q000235:genetics
chemical_list: C519848:BRK1 protein, human; D003598:Cytoskeletal Proteins; C499905:FANCD2 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human