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.
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.
Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
F J
FJ
Hes
R B
RB
van der Luijt
A L W
AL
Janssen
R A
RA
Zewald
G J
GJ
de Jong
J W
JW
Lenders
T P
TP
Links
G P M
GP
Luyten
R H
RH
Sijmons
H J
HJ
Eussen
D J J
DJ
Halley
C J M
CJ
Lips
P L
PL
Pearson
A M W
AM
van den Ouweland
D F
DF
Majoor-Krakauer
D015139:Blotting, Southern; D004252:DNA Mutational Analysis; D005787:Gene Frequency; D018095:Germ-Line Mutation; D006801:Humans; D021141:Nucleic Acid Amplification Techniques; D010375:Pedigree; D015995:Prevalence; D017422:Sequence Analysis, DNA; D006623:von Hippel-Lindau Disease / Q000175:diagnosis* / Q000235:genetics*