Germline mutations in von Hippel_Lindau (VHL) gene in patients from Poland. Disease presentation in patients with deletions of the entire VHL gene

• Thirty-four Polish families with a clinical diagnosis of VHL disease were studied in order to describe: (1) the frequency of germline mutations in these families; (2) the spectrum of germline VHL mutations in the Polish population; (3) the proportion of de novo mutations; and (4) genotype-phenotype correlations in patients with a deletion of the entire VHL gene. • The coding region of the VHL gene was tested using direct sequencing. Large deletions were analysed using quantitative Southern blotting and/or multiplex PCR. • (1) Germline VHL mutations were observed in 30/34 (88%) families. Mutations were not identified in 4/34 (12%) probands (five subjects/four families) with central nervous system haemangioblastoma (cHAB) and/or retinal angioma (rHAB). (2) Small intragenic mutations were detected in 18/30 (60%) families; all were located 3′ of codon 53. Partial and complete gene deletions were detected in 7/30 (23%) and 5/30 (17%) families, respectively. Five mutations were unique to the Polish population. (3) Five of 30 (17%) VHL mutation positive probands were found to have no family history of VHL. (4) Of 11 patients with complete deletions, all developed cHAB, two presented with rHAB, and none developed renal cell carcinoma (RCC). • (1) Some patients with predominantly brain tumours and/or retinal angioma do not have identifiable germline mutations in the VHL gene and may have somatic mosaicism, or may be affected by mutations of different nature or localisation than the mutations for which the study assays are designed, or may be phenocopies of the disease. An alternative explanation is the presence of additional haemangioblastoma susceptibility genes. (2) The main characteristics of germline VHL mutations in the Polish population are similar to those reported in other populations. However, we observed a higher proportion of patients with complete deletions (5/30, 17%), compared to those reported in other populations (3-9%). There was no evidence of a founder effect for complete deletions in our patients. (3) The apparent de novo mutation rate is ∼20%. (4) A complete deletion of the VHL gene results primarily in brain tumours. This result may be useful in genetic counselling for subjects with complete deletions.