A novel pathogenic germline chromosome 3 inversion in von Hippel-Lindau disease.

Abstract

von Hippel-Lindau (VHL) is an autosomal-dominant hereditary tumour susceptibility disease associated with pathogenic germline variants in the <i>VHL</i> tumour suppressor gene. VHL patients are at increased risk of developing multiple benign and malignant tumours. Current CLIA-based genetic tests demonstrate a very high detection rate of germline <i>VHL</i> variants in patients with clinical manifestations of VHL. In this report, we describe a large family with canonical VHL manifestations, for which no germline alteration had been detected by conventional germline testing. We identified a novel 291 kb chromosomal inversion involving chromosome 3p in affected family members. This inversion disrupts the <i>VHL</i> gene between exon 2 and exon 3 and is thereby responsible for the disease observed in this family.