Frequency of Von Hippel-Lindau germline mutations in classic and non-classic Von Hippel-Lindau disease identified by DNA sequencing, Southern blot analysis and multiplex ligation-dependent probe amplification

Clin Genet. 2007 Aug;72(2):122-9. doi: 10.1111/j.1399-0004.2007.00827.x.


The current clinical diagnosis of Von Hippel-Lindau (VHL) disease demands at least one specific [corrected] VHL manifestation in a patient with familial VHL disease, or, in a [corrected] sporadic patient, at least two or more hemangioblastomas or a single hemangioblastoma in combination with a typical visceral lesion. To evaluate this definition, we studied the frequency of germline VHL mutation in three patients groups: (i) multi-organ involvement (classic VHL), (ii) limited VHL manifestations meeting criteria (non-classic VHL) and (iii) patients with VHL-associated tumors not meeting current diagnostic VHL criteria. In addition, we validated multiplex ligation-dependent probe amplification (MLPA) as a rapid and reliable quantitative method for the identification of germline VHL deletions. The frequency of germline VHL mutations was very high in classic VHL cases with multi-organ involvement (95%), lower in non-classic cases that meet current diagnostic criteria but have limited VHL manifestations or single-organ involvement (24%) and low (3.3%), but tangible in cases not meeting current diagnostic VHL criteria. The detection of germline VHL mutations in patients or families with limited VHL manifestations, or single-organ involvement is relevant for follow-up of probands and early identification of at-risk relatives.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Southern
  • DNA Mutational Analysis
  • Gene Frequency*
  • Germ-Line Mutation*
  • Humans
  • Nucleic Acid Amplification Techniques
  • Pedigree
  • Prevalence
  • Sequence Analysis, DNA
  • von Hippel-Lindau Disease / diagnosis*
  • von Hippel-Lindau Disease / genetics*