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 VHL 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 VHL 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 VHL gene between exon 2 and exon 3 and is thereby responsible for the disease observed in this family.

Keywords: Chromosome Aberrations; Gene Rearrangement; Genetic Diseases, Inborn; Human Genetics; Urology.

Figure 1. Family pedigree with patient imaging and histology. (A) The family pedigree showed four generations with the clinical features of von Hippel-Lindau highlighted in evaluated patients. The presence of the germline chromosome 3p inversion was denoted by a filled black circle for carriers and an empty circle for those who tested negative for the inversion. (B) Imaging of example kidney tumours is shown for patients III:1, III:25, and III:35 with example histological staining from those patients’ tumours showing clear cell renal cell carcinomas. CNS, central nervous system; ELST, endolymphatic sac tumour.

Figure 2. Mapping of germline chromosome 3 inversion. A germline inversion on chromosome 3p was identified resulting in the flipping of approximately 291 kb of DNA that disrupted the VHL gene. Both breakpoints were mapped by DNA sequencing and occurred within Alu repeats, AluY at Hg19 chr3:9898876–9899184 and AluYa5 at Hg19 chr3:10189995–10190297.