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Online mutation report
High frequency of novel germline mutations in the VHL gene in the heterogeneous population of Brazil
  1. J C C Rocha1,2,
  2. R L A Silva2,
  3. B B Mendonça3,
  4. S Marui3,
  5. A J G Simpson2,
  6. A A Camargo2
  1. 1Department of Oncogenetics, Hospital do Câncer A C Camargo, São Paulo, Brazil
  2. 2Laboratory of Cancer Genetics, Ludwig Institute for Cancer Research, São Paulo, Brazil
  3. 3Laboratory of Hormones and Molecular Genetics, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
  1. Correspondence to:
 Dr J C C Rocha, Rua Professor Antonio Prudente 109, 4th floor, 01509-010 São Paulo, SP, Brazil;
 jccrocha{at}ludwig.org.br

https://doi.org/10.1136/jmg.40.3.e31

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    Von Hippel-Lindau disease (VHL) (MIM 193300) is a heritable autosomal dominant disease characterised by predisposition to the development of a combination of benign and malignant tumours affecting multiple organs. The main features of the disease include retinal angiomas (RA), haemangioblastomas of the central nervous system (HB), clear cell renal carcinomas (RC), phaeochromocytomas (PH), multiple renal and pancreatic cysts, adenomas and carcinomas of the pancreas, neuroendocrine tumours, endolymphatic sac tumours, and papillary cystadenomas of the epididymis and broad ligaments.1–5 Reported birth incidence ranges from 1:36 000 to 1:45 000.6–8 Penetrance is essentially complete at 65 years of age and subjects at risk may develop a combination of clinical manifestations during their lifetime.6

    Key points

    • Von Hippel-Lindau (VHL) disease (MIM 193300) is an autosomal dominant disorder caused by germline mutations in the VHL gene that predisposes to development of retinal and central nervous system haemangioblastomas, renal cell carcinomas, pancreatic tumours, phaeochromocytoma, as well as multiple cysts of the kidneys and pancreas.

    • We report here the analysis of 20 patients with VHL, mainly from Brazil (17 familial and three without a family history), in whom we detected germline VHL gene mutations in every case using a combination of direct sequencing and quantitative Southern blotting.

    • The mutations consisted of 16 point mutations (nine missense, three frameshift, one in frame deletion, two splice defects, and one nonsense mutation), three partial deletions, and one complete deletion of the VHL gene. As observed in other populations, the presence of PH (type 2 phenotype) was associated with the presence of a full length but mutated protein, whereas VHL without PH (type 1 phenotype) resulted from a truncated protein. Point mutations tended to concentrate within exons 1 and 2 (87.5%), a high proportion of which were novel (50%).

    • The molecular analyses of germline mutations …

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