VHL mosaicism: the added value of multi-tissue analysis

Leslie E Oldfield; Jessica Grzybowski; Sylvie Grenier; Elizabeth Chao; Gregory S Downs; Kirsten M Farncombe; Tracy L Stockley; Ozgur Mete; Raymond H Kim

doi:10.1038/s41525-022-00291-3

VHL mosaicism: the added value of multi-tissue analysis

NPJ Genom Med. 2022 Mar 18;7(1):21. doi: 10.1038/s41525-022-00291-3.

Authors

Leslie E Oldfield¹, Jessica Grzybowski², Sylvie Grenier³, Elizabeth Chao², Gregory S Downs³, Kirsten M Farncombe⁴, Tracy L Stockley^{3

5}, Ozgur Mete¹, Raymond H Kim⁶

Affiliations

¹ Princess Margaret Cancer Centre, Toronto, ON, Canada.
² Ambry Genetics, Aliso Viejo, CA, USA.
³ Division of Clinical Laboratory Genetics, Laboratory Medicine Program, University Health Network, Toronto, ON, Canada.
⁴ Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada.
⁵ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
⁶ Princess Margaret Cancer Centre, University Health Network, Sinai Health System, Hospital for Sick Children, Department of Medicine, University of Toronto, Toronto, ON, Canada. raymond.kim@uhn.ca.

Abstract

Von Hippel-Lindau disease (VHL) is an autosomal dominant, inherited syndrome with variants in the VHL gene causing predisposition to multi-organ benign and malignant neoplasms. A germline VHL variant is identified in 95-100% of individuals with a clinical diagnosis of VHL. Here, we present the case of an individual with a clinical diagnosis of VHL disease where peripheral blood DNA analysis did not detect a VHL variant. Sequencing of four tumor tissues (ccRCC, pheochromocytoma, lung via sputum, liver) revealed a VHL c.593 T > C (p.Leu198Pro) variant at varying allele fractions (range: 10-55%) in all tissues. Re-examination of the peripheral blood sequencing data identified this variant at 6% allele fraction. Tumor analysis revealed characteristic cytomorphological, immunohistochemical reactivity for alpha-inhibin, and CAIX, and reduced pVHL reactivity supported VHL-related pseudohypoxia. This report of a rare case of VHL mosaicism highlights the value of tissue testing in VHL variant negative cases.