Identification of 3 novel VHL germ-line mutations in Danish VHL patients.
BACKGROUND
von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome in which the patients develop retinal and central nervous system hemangioblastomas, pheochromocytomas and clear-cell renal tumors. The autosomal dominant disease is caused by mutations in the VHL gene.


METHODS
VHL mutational analysis was carried out by sequencing of the coding sequence and by multiplex ligation-dependent probe amplification analysis. The functional consequence of the variants was investigated using in silico prediction tools.


RESULTS
A total of 289 probands suspected of having VHL syndrome have been screened for mutations in the VHL gene. Twenty-six different VHL mutations were identified in 36 families including one in-frame duplication, two frame-shift mutations, four nonsense mutations, twelve missense mutations, three intronic mutations and four large genomic rearrangements. Three of these mutations (c.319 C > T, c.342_343dupGGT and c.520_521dupAA) were novel.


CONCLUSIONS
In this study we report the VHL germ-line mutations found in Danish families. We found three novel VHL mutations where two were classified as pathogenic and the latter was classified as a variant of unknown significance. Together, our findings contribute to the interpretation of the potential pathogenicity of VHL germ-line mutations.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Denmark.
Mette
M
Dandanell
Lennart
L
Friis-Hansen
Lone
L
Sunde
Finn C
FC
Nielsen
Thomas V O
TV
Hansen
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis / Q000379:methods; D003718:Denmark; D005260:Female; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010375:Pedigree; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*; D055815:Young Adult; D006623:von Hippel-Lindau Disease / Q000235:genetics*
D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human