The current clinical diagnosis of Von Hippel-Lindau (VHL) disease demands at least one specific a sporadic VHL manifestation in a patient with familial VHL disease, or, in asporadic 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.

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Keywords De novo mutations, Genetic testing, Genotype, MLPA, Non-penetrance, Phenotype correlations, Sporadic VHL disease, Von Hippel-Lindau (VHL) disease
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Hes, F.J, van der Luijt, R.B, Janssen, A.L.W, Zewald, R.A, de Jong, G.J, Lenders, J.W, … Majoor-Krakauer, D.F. (2007). 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. Clinical Genetics: an international journal of genetics and molecular medicine, 72(2), 122–129. doi:10.1111/j.1399-0004.2007.00827.x