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Genotype–phenotype correlations in von Hippel‐Lindau disease
Author(s) -
Ong Kai Ren,
Woodward Emma R.,
Killick Pip,
Lim Caron,
Macdonald Fiona,
Maher Eamonn R.
Publication year - 2007
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.20385
Subject(s) - missense mutation , von hippel–lindau disease , biology , frameshift mutation , genetics , genotype , pheochromocytoma , cancer research , nonsense mutation , disease , phenotype , mutation , medicine , gene , endocrinology
Abstract von Hippel‐Lindau (VHL) disease is a dominantly inherited familial cancer syndrome resulting from mutations in the VHL tumor suppressor gene. VHL disease displays marked variation in expression and the presence of pheochromocytoma has been linked to missense VHL mutations. We analyzed genotype–phenotype correlations in 573 individuals with VHL disease. Routine clinical and radiological surveillance of VHL patients and at‐risk relatives was associated with increased detection of retinal angiomatosis (73 vs. 59% of cases) and a reduction in age at diagnosis of renal cell carcinoma (RCC) (44.0±10.9 vs. 39.7±10.3 years). We confirmed the association of pheochromocytoma with missense mutations described previously, but stratifying missense mutations into those that resulted in substitution of a surface amino acid and those that disrupted structural integrity demonstrated that surface amino acid substitutions conferred a higher pheochromocytoma risk. Age at first manifestation of VHL disease was significantly earlier (P=0.001), and age‐related risks of retinal angiomas and RCC were higher (P=0.022 and P=0.0008, respectively) in individuals with a nonsense or frameshift mutation than in those with deletions or missense mutations that disrupted the structural integrity of the VHL gene product (pVHL). These results extend genotype–phenotype–protein structure correlations in VHL disease and provide a baseline for future chemoprevention studies in VHL disease. Hum Mutat 28(2), 143–149, 2007. © 2006 Wiley‐Liss, Inc.