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

摘要

• Thirty-four Polish families with a clinical diagnosis of\udVHL disease were studied in order to describe: (1) the\udfrequency of germline mutations in these families; (2) the\udspectrum of germline VHL mutations in the Polish population; (3) the proportion of de novo mutations; and (4)\udgenotype-phenotype correlations in patients with a\uddeletion of the entire VHL gene.\ud• The coding region of the VHL gene was tested using\uddirect sequencing. Large deletions were analysed using\udquantitative Southern blotting and/or multiplex PCR.\ud• (1) Germline VHL mutations were observed in 30/34\ud(88%) families. Mutations were not identified in 4/34\ud(12%) probands (five subjects/four families) with central\udnervous system haemangioblastoma (cHAB) and/or\udretinal angioma (rHAB). (2) Small intragenic mutations\udwere detected in 18/30 (60%) families; all were\udlocated 3′ of codon 53. Partial and complete gene\uddeletions were detected in 7/30 (23%) and 5/30\ud(17%) families, respectively. Five mutations were unique\udto the Polish population. (3) Five of 30 (17%) VHL mutation positive probands were found to have no family\udhistory of VHL. (4) Of 11 patients with complete\uddeletions, all developed cHAB, two presented with\udrHAB, and none developed renal cell carcinoma (RCC).\ud• (1) Some patients with predominantly brain tumours\udand/or retinal angioma do not have identifiable germline mutations in the VHL gene and may have somatic\udmosaicism, or may be affected by mutations of different\udnature or localisation than the mutations for which the\udstudy assays are designed, or may be phenocopies of\udthe disease. An alternative explanation is the presence\udof additional haemangioblastoma susceptibility genes.\ud(2) The main characteristics of germline VHL mutations\udin the Polish population are similar to those reported in\udother populations. However, we observed a higher proportion of patients with complete deletions (5/30,\ud17%), compared to those reported in other populations\ud(3-9%). There was no evidence of a founder effect for\udcomplete deletions in our patients. (3) The apparent de\udnovo mutation rate is ∼20%. (4) A complete deletion of\udthe VHL gene results primarily in brain tumours. This\udresult may be useful in genetic counselling for subjects\udwith complete deletions.