title: Clinical and molecular characterization of Brazilian families with von Hippel-Lindau disease: a need for delineating genotype-phenotype correlation.
abstract: von Hippel-Lindau (VHL) disease is an autosomal dominant hereditary cancer syndrome that predisposes to the development of a variety of benign and malignant tumours, especially cerebellar haemangioblastomas, retinal angiomas and clear-cell renal cell carcinomas (RCC). The etiology and manifestations are due to germline and somatic mutations in the VHL tumour suppressor gene. VHL disease is classified into type 1 and type 2, showing a clear genotype-phenotype correlation, as type 2 is associated with phaeochromocytoma and essentially caused by missense mutations. The aim of this study is to characterize the phenotype and genotype of families with VHL disease. Eighteen of twenty patients from ten unrelated families underwent genetic testing, nine of them fulfilled VHL disease criteria and one had an apparently sporadic cerebellar haemangioblastoma. Four different germline mutations in the VHL gene were identified: c.226_228delTTC (p.Phe76del); c.217C > T (p.Gln73X); IVS1-1 G > A and IVS2-1 G > C. The first three mutations were associated with type 1 disease and the last one with type 2B, which had never been identified in the germline. The transcriptional processing of a novel splice-site mutation was characterised. Three type 1 VHL families showed large deletions of the VHL gene, two of them encompassed the FANCD2/C3orf10 genes and were not associated with renal lesions. We also suggest that such families should be subclassified according to the risk of RCC and the extent of the VHL gene deletions. This study highlights the need for a through clinical and molecular characterisation of families with VHL disease to better delineate its genotype-phenotype correlation.
authors.affiliation: Department of Genetics, Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil. isgomy@gmail.com
authors.forename: Israel
authors.initials: I
authors.lastname: Gomy
authors.forename: Greice Andreotti
authors.initials: GA
authors.lastname: Molfetta
authors.forename: Ester
authors.initials: E
authors.lastname: de Andrade Barreto
authors.forename: Cristiane Ayres
authors.initials: CA
authors.lastname: Ferreira
authors.forename: Dalila Luciola
authors.initials: DL
authors.lastname: Zanette
authors.forename: José Cláudio
authors.initials: JC
authors.lastname: Casali-da-Rocha
authors.forename: Wilson Araujo
authors.initials: WA
authors.lastname: Silva
mesh_terms: D000293:Adolescent; D000328:Adult; D001938:Brazil; D002292:Carcinoma, Renal Cell / Q000150:complications / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D002528:Cerebellar Neoplasms / Q000150:complications / Q000235:genetics / Q000473:pathology; D002648:Child; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D005190:Family; D005260:Female; D017353:Gene Deletion; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007438:Introns; D007680:Kidney Neoplasms / Q000150:complications / Q000235:genetics* / Q000473:pathology; D008297:Male; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D012307:Risk Factors; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*; D055815:Young Adult; D006623:von Hippel-Lindau Disease / Q000150:complications / Q000235:genetics* / Q000473:pathology
chemical_list: D004273:DNA, Neoplasm; D051794:Von Hippel-Lindau Tumor Suppressor Protein