Germline mutations in the Von Hippel-Lindau (VHL) gene

Introduction Von Hippel-Lindau (VHL) disease is a complex, autosomal, dominant inherited disorder, variably presenting with retinal and cerebellar haemangioblastoma, renal cell carcinoma, phaeochromocytoma and endolymphatic sac tumours. Cysts and cystadenoma may develop in kidney, pancreas and epididymis. Germline mutations in the VHL tumour suppressor gene are found in most of the families fulfilling the clinical diagnostic criteria of VHL disease. Objective To summarise the results of mutation analysis of the VHL gene in familial and sporadic cases of VHL disease diagnosed in the Netherlands. Patients and methods Familial (n=25) and sporadic (n=7) VHL patients, as well as sporadic patients (n=2) with VHL-related tumours, not fulfilling current diagnostic criteria for VHL disease, were investigated by direct sequencing of the coding region, quantitative Southern blot analysis and Fluorescence in Situ Hybridisation (FISH) of the VHL gene. Results We report 34 VHL germline mutations, including eight novel germline mutations in the open reading frame of the VHL gene. Analyses of genotype-phenotype correlations were consistent with previous reports. In nine sporadic patients with a VHL germline mutation we could identify four de novo VHL gene mutations. In four of the nine sporadic patients the parents were not available for testing. One of the nine patients shared a VHL germline mutation with a clinically unaffected parent (age 77 years) suggesting non-penetrance of VHL disease. Family histories of VHL in two other families were suggestive for reduced penetrance of VHL germline mutations. Conclusions These results indicate that at least 12% of the germline mutations in the VHL gene occur de novo. Germline mutations are found in patients not fulfilling the currently accepted diagnostic criteria for VHL disease. Absence of VHL symptoms in carriers of VHL germline mutations indicate reduced penetrance and has implications for genetic counselling. VHL germline mutations in the Netherlands