Detailed mapping of germline deletions of the von Hippel--Lindau disease tumour suppressor gene

Von Hlppel-Llndau disease is a domlnantly Inherited familialcancer syndrome characterised by the development of retinalangiomatosis, cerebellar and spinal hemangloblastoma, renalcell carcinoma, phaeochromocytoma and pancreatic tumours. AcDNA (g7) which detects frequent genomic rearrangements in VHLdisease patients on Southern analysis, and contains the partialcoding sequence of the VHL gene has been isolated recently.To characterise the nature of the genomic rearrangements inVHL disease we initially screened 116 patients with VHL diseaseand identified 22 patients (19%) with abnormal fragments InEcoR1 digested DNA probed with g7. We then established thatthe coding sequence contained within g7 is represented in 3exons, and designed exon specific probes to investigate the22 patients with genomic rearrangements. All 22 patients weredemonstrated to have germline deletions, but the deletions wereheterogeneous with 7 patients having deletions confined to the5' exon 1, and 8 with non-overlapping deletions of exon 3. In7 unrelated patients, including 2 new mutations, the germilnedeletions were similar in size and position. There was no relationshipbetween the clinical phenotype and the deletion of individualexons. Although phaeochromocytoma was less frequent in kindredswith germllne deletions than those without detectable deletions,the difference was not statistically significant (1/19 versus16/72 respectively, x² = 1.84 p<0.1).