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

• Published in: Clinical genetics 2007-08, Vol.72 (2), p.122-129
• Main Authors: Hes, FJ, van der Luijt, RB, Janssen, ALW, Zewald, RA, de Jong, GJ, Lenders, JW, Links, TP, Luyten, GPM, Sijmons, RH, Eussen, HJ, Halley, DJJ, Lips, CJM, Pearson, PL, van den Ouweland, AMW, Majoor-Krakauer, DF
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Blotting, Southern; de novo mutations; DNA Mutational Analysis; Fundamental and applied biological sciences. Psychology; Gene Frequency; General aspects. Genetic counseling; genetic testing; Genetics of eukaryotes. Biological and molecular evolution; genotype; Germ-Line Mutation; Humans; Medical genetics; Medical sciences; MLPA; Molecular and cellular biology; non-penetrance; Nucleic Acid Amplification Techniques; Pedigree; phenotype correlations; Prevalence; Sequence Analysis, DNA; sporadic VHL disease; Von Hippel-Lindau (VHL) disease; von Hippel-Lindau Disease - diagnosis; von Hippel-Lindau Disease - genetics
• ISSN: 0009-9163; 1399-0004
• DOI: 10.1111/j.1399-0004.2007.00827.x

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.