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

Author:

Vocke, Cathy D [ORCID]

Ricketts, Christopher J

Pack, Svetlana

Raffeld, Mark

Hewitt, Stephen

Lebensohn, Alexandra P

O'Brien, Lidenys

Gautam, Rabindra

Reynolds, Krista

Schmidt,Laura

Choo, Kristin

Kenigsberg, Alex

Gurram, Sandeep

Chew, Emily Y

Nilubol, Naris

Chittaboina, Prashant

Merino, Maria J

Ball, Mark W

Linehan, W Marston [ORCID]
Author Address

Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA., Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA., Cancer Genetic Branch, National Institutes of Health, Bethesda, Maryland, USA., Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA., Division of Epidemiology and Clinical Applications, National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA., Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA., Neurosurgery Unit for Pituitary and Inheritable Diseases, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA., Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA WML@nih.gov.,

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.

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Author Address